Neuroimmune Interactions in Inflammatory Skin and Intestinal Diseases

Abstract

The nervous and immune systems engage in intricate bidirectional interactions that constitute a central hub in the pathogenesis of cutaneous and intestinal inflammation. As primary barrier organs, the skin and gut share analogous structural and immunological features and are functionally linked through an integrated neuroimmune network and shared inflammatory signaling, forming the “skin-gut axis”. Nevertheless, comprehensive and systematic reviews that simultaneously address neurogenic inflammation in both the cutaneous and intestinal compartments remain scarce, and translational research targeting their reciprocal crosstalk is hampered by insufficient clinical evidence and inadequate target precision. In this narrative review, we focus on the neuroimmune mechanisms underlying neurogenic skin disorders, including atopic dermatitis, psoriasis, and rosacea. Given the strong association between intestinal inflammation and infection, we further summarize neuroimmune interactions in gut infectious inflammation, with particular emphasis on the unique innervation patterns of the intestine. Additionally, we discuss therapeutic strategies that target convergent and clinically relevant neuroimmune circuits shared by skin and gut inflammation. This review aims to provide a theoretical framework for deciphering the neuroimmune pathogenesis and stereotyped interconnections between skin and gut inflammation, and to inspire novel anti-inflammatory approaches that specifically modulate neuroimmune pathways.

Graphical Abstract

Introduction

The nervous system and the immune system are closely linked, and they may have evolved together, using the same molecules and receptors for information transmission.¹ Neuron-immune interactions involve complex interplays between the nervous system and the immune system, including both the peripheral nervous system (PNS) and the central nervous system (CNS). Within the PNS, sensory nerves, sympathetic nerves, vagus nerves, and enteric nerves can signal to immune cells, influencing the immune cells in organs such as the skin, intestines, and lungs, and eliciting specific responses.^2,3 Abundant research has demonstrated the relationship between neuro-immunity and inflammation; pain during inflammation is closely linked to neuro-immunity.⁴ Neurogenic inflammation of the skin is a significant factor in inflammatory skin diseases like Atopic Dermatitis (AD).⁵ Furthermore, neuro-immunity can impact intestinal inflammation via the gut-brain axis,⁶ thereby further affecting the occurrence and progression of gastrointestinal disorders such as inflammatory bowel disease (IBD).⁷

Accumulating clinical and experimental evidence has confirmed a close bidirectional interaction between the skin and the gut, a concept now referred to as the skin‑gut axis. This concept provides a unified framework for explaining the frequent comorbidity of skin and intestinal diseases and their common pathological characteristics.⁸ Both organs serve as major barrier surfaces of the body. They exhibit similar structural components and immune compositions, including epithelial barriers, networks of nerve fibers, and resident immune cell populations. Functional disorders of them often manifest clinically as parallel inflammatory phenotypes.^9,10 Mechanistically, bidirectional communication along the skin-gut axis may be achieved via integrated neuroimmune networks, microbial metabolites and systemic inflammatory signals: the autonomic nervous system and visceral sensory pathways can directly transmit signals between the skin and gut to regulate local immune cell activation, cytokine secretion and barrier integrity.^11,12 For example, cutaneous sensory nerve fibers release neuropeptides such as substance P (SP) and calcitonin gene-related peptide (CGRP). These neuropeptides can not only regulate local cutaneous immunity, but also relay signals to the central nervous system via spinal afferent pathways, and subsequently modulate the function of intestinal immune cells through autonomic efferent fibers, which may constitute one of the mechanisms of bidirectional skin-gut communication.^9,12 Conversely, after sensing changes in the intestinal microenvironment, intestinal vagal afferent fibers activate the cholinergic anti-inflammatory pathway (CAIP) via the nucleus tractus solitarius and dorsal motor nucleus, leading to acetylcholine release. Acetylcholine may act on α7 nicotinic acetylcholine receptors (α7nAChR) on the surface of skin macrophages and mast cells to suppress cutaneous inflammatory responses.^13,14 Meanwhile, immune cell migration, shared antigenic triggers, and systemic immune polarization further amplify inflammatory responses between the two sites. Direct experimental evidence has confirmed that intestinal dysbiosis diminishes regulatory T cells and expands Th17 cells; such cells may migrate through the blood circulation and participate in the progression of cutaneous inflammation.¹⁵ Intestinal nerves generate divergent functional effects after sensing local signals. This discrepancy may hinge on two factors: what specific alterations arise in the gut microenvironment, and whether these changes overwhelm the gut’s intrinsic regulatory capacity. These interconnected pathways link gut dysbiosis, barrier dysfunction, and immune imbalance with skin inflammation, indicating the critical role of neuroimmune interactions in mediating the skin‑gut axis. Therefore, approaching neuroimmune crosstalk in the context of skin and intestinal inflammation as two integral domains facilitates a holistic understanding of the skin-gut axis and the sophisticated bidirectional regulation between the nervous and immune systems.

The present review addresses the role of neuroimmune interactions in modulating cutaneous and intestinal inflammation, with an emphasis on inflammatory diseases. To ensure comprehensiveness and accuracy, we searched PubMed and other primary databases, supplemented by manual bibliography tracing, covering publications up to 2026, and included original studies, reviews, and clinical guidelines. This review provides a detailed mechanistic discussion of key neurogenic skin inflammations, including AD and psoriasis, and systematically delineates the associations between intestinal neuroimmunity and inflammation from four neural perspectives: the dorsal root ganglia (DRG), vagus nerve, sympathetic nerves, and the enteric nervous system (ENS). Unlike other neuroimmune reviews, this article innovatively adopts a “skin-gut axis” framework to examine neuroimmune crosstalk and summarizes current therapeutic strategies that target shared, crucial mechanistic circuits in both skin and gut inflammation.

Nevertheless, despite extensive research efforts, several challenges remain. The inherent heterogeneity of skin and intestinal inflammation may lead to considerable variations in neuroimmune mechanisms under specific disease conditions, and the differences in neuroimmune signaling between homeostasis and inflammatory states also warrant close attention. Moreover, many mechanistic insights are derived from animal experiments, posing substantial difficulties in translating these findings into actionable therapeutic targets. Currently available targeted strategies are hampered by insufficient clinical evidence and suboptimal specificity.

The Mechanism of Neuro-Immunity in Skin Inflammation

The Neuroimmune Interactions in Skin Barrier Tissues

Immune cells and neurons can co-locate and interact at discrete anatomical sites, thereby driving tissue protection and physiological processes.¹⁶ Neuroimmune interactions are mainly mediated by soluble factors such as neurotransmitters, neuropeptides, and cytokines.¹⁷ Immune cells respond to neuronal signals by expressing neurogenic molecular receptors, while neurons express immune-derived cytokines and neurotransmitter receptors, which can affect neuronal function.^18–20 Immune cells aggregate near nerve fibers in barrier tissues, expressing neuropeptide and neurotransmitter receptors, and interact with neurons to regulate the immune environment. Neuroimmune interactions serve as important immunoregulatory hubs in the physiological and pathological states of barrier tissues.^21,22

The PNS is roughly described in two major systems: (a) the autonomic nervous system (ANS), which controls various unconscious physiological processes such as heart rate, respiration rate, and digestion; (b) the somatic sensory nervous system, which transmits information from various tissues back to the spinal cord and brain. Compared to the somatic sensory nervous system which mediates conscious perception of touch, pain, and itch, the ANS primarily functions unconsciously and is further subdivided into the sympathetic nervous system, the parasympathetic nervous system and the ENS.²³ The sympathetic nervous system originates from the spinal cord and primarily induces adrenaline-related physiological responses associated with the “fight or flight” reaction through the release of norepinephrine (NE). Meanwhile, the parasympathetic nervous system, originating from the medulla and sacral spinal cord, utilizes the neurotransmitter acetylcholine (ACh) to mediate cholinergic rest-digest responses.²⁴ The somatic sensory nervous system is responsible for regulating sensory functions, including touch and pain. Special subgroups of somatic sensory neurons include nociceptors and itch receptors, which are responsible for detecting stimuli associated with injury or itch induction. The activation of nociceptors and itch receptors is often accompanied by immune and inflammatory responses.²⁵ Different parts of the PNS coordinate with each other to respond jointly to external stimuli, thus maintaining the homeostasis of skin barrier tissues.

Skin is one of the largest organs in the human body. Serving as the first line of defense, it plays a crucial role in maintaining internal homeostasis, providing barrier function, and resisting the invasion of pathogens.²⁶ Skin nerve fibers are closely associated with various cells in the skin, including keratinocytes, fibroblasts, endothelial cells, Schwann cells and resident immune cells.⁹ Nerve fibers in the epidermis release neuropeptides to stimulate keratinocytes to secrete pro-inflammatory cytokines such as IL-1α, IL-6, and IL-8, while secreting neuropeptide SP to enhance the migration and antigen presentation of Langerhans cells (LCs), thereby promoting allergic sensitization.^27–29 Clinical morphological observations reveal that dermal sensory nerve fibers often interweave with adrenergic and cholinergic nerve fibers that secrete neuropeptide Y (NPY) and vasoactive intestinal peptide (VIP), and lie in close proximity to dermal mast cells, blood vessels and hair follicles; cutaneous sensory nerve fibers (CSNF) are distributed across both the dermis and epidermis and constitute the principal component of cutaneous nerves.⁹ CSNF originates from the DRG of the spinal cord or trigeminal ganglia. DRG neurons transmit fibers throughout the trunk skin, conveying nerve signals to the dorsal horn of the spinal cord, where the signals are then transmitted to the brainstem and thalamus. Trigeminal ganglia neurons innervate the skin of the head and face. CSNF is responsible for sensory functions, including touch, thermal sensation, mechanical sensation, proprioception, stretch, itch, and pain.^30,31 The ANS innervating the skin is primarily sympathetic, representing only a small portion of nerve fibers within the skin, which are mainly confined to the dermis, regulating hair follicles, blood vessels, lymphatic vessels, eccrine glands, apocrine glands, and arrector pili muscles.^30,32 Based on the diameter and transmission velocity of skin nerve fibers, nerve endings can be distinguished into three types: Aβ, Aδ, and C fibers, which regulate various sensations by encoding pain, itch, temperature, pressure, location, and vibration signals.³³ Moreover, these nerve fibers are anatomically close to functional immune cells that provide a basis for neuroimmune interactions in the skin.^2,34 The study shows that there is a close association between pruritic diseases and immune cells. For instance, mast cells are associated with various types of itch, as they can release pruritogens.³⁵ Activated neurons release neuropeptides and neurotransmitters, which can act on microvascular cells and resident mast cells, causing mast cell degranulation, leading to physiological responses such as vasodilation, plasma extravasation, and leukocyte infiltration.^36–38 Therefore, the skin is a systemic organ that requires a network of neuroimmune interactions to maintain its homeostasis.

The skin contains a large number of resident immune cells, including macrophages, mast cells, dendritic cells (DCs), γδ T cells and innate lymphoid cells (ILCs). These cells have unique functions and can resist pathogens on the surface of the skin and mediate wound healing.¹⁰ Macrophages are the most widely distributed and abundant immune cell population in the steady-state barrier tissue of the skin and are crucial sentinels for detecting skin tissue damage and pathogens. Moreover, macrophages can attract other immune cells from the circulatory system to the site of injury by expressing chemotactic factors and secreting cytokines, aiding in the repair of damaged tissue.³⁹ Additionally, macrophages constitutively express neurotrophic factors such as nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) to maintain neuronal growth and survival. Neuronal peptides released by neurons can regulate macrophage function and cytokine release, emphasizing the importance of bidirectional communication between neurons and macrophages in maintaining skin barrier homeostasis.^40–42 In mouse models, upon ultraviolet radiation exposure, cutaneous GINIP+ sensory neurons stimulate embryonic-derived tissue-resident TIM4+ macrophages to secrete IL-10. IL-10 sustains macrophage survival and suppresses inflammation. Cutaneous GINIP+ neurons release the neuropeptide TAFA4, which induces dermal macrophages to produce IL-10. The TAFA4/IL-10 axis supports the survival of IL-10+TIM4+ macrophages, alleviating cutaneous inflammation and facilitating tissue repair.⁴³ Moreover, the TAFA4-IL-10 axis activation facilitates the survival of IL-10⁺TIM4⁺ dermal macrophages, alleviating skin inflammation and promoting tissue regeneration.⁴³

Mast cells in the skin are typically associated with Th2-type reactions and IgE-mediated allergic inflammation. Additionally, mast cells participate in wound healing, pathogen defense, and contact hypersensitivity reactions.⁴⁴ Biologically active substances released by neurons such as NGF and SP can activate mast cells to further influence neuronal function.³⁶ Mast cells contain granules enclosing many mediators, including histamine, neutral proteases, cytokines [such as tumor necrosis factor (TNF)], growth factors [such as vascular endothelial growth factor (VEGF)], and chemotactic factors. Mast cells release these mediators into the extracellular space by degranulation, participating in various physiological and pathological processes.^39,45 Studies using mouse cell lines have verified that mast cells can form physical neuroimmune synapses with neurons, and their binding relies on the reciprocal expression of integrins including N-cadherin, nectin 3 and cell adhesion molecule 1 (CADM1). As a homophilic adhesion molecule spanning the synaptic cleft, CADM is highly enriched at contact sites between mast cells and axons.⁴⁶ Therefore, we hypothesize that mast cell granules can be transferred to neurons via two pathways: direct fusion of granules with the neuronal cell membrane, or neuronal uptake of insoluble granule residues released by mast cells.^47–49 Mast cells can regulate the local microenvironment and neuronal function through these transgranular processes, such as the direct transfer of heparin. Another potential role of transgranulation is providing mediators to neurons, such as liberating gonadotropin-releasing hormone.⁴⁷ Regulatory transport between mast cells and neurons may dictate the functional bias of these cells. They could either mediate inflammatory immune reactions or facilitate tissue defense and repair.

DCs in the skin are divided into two main types: LCs and dermal dendritic cells (dDCs). LCs are located in the epidermis, interwoven with keratinocytes, facilitating monitoring of environmental changes.⁵⁰ dDCs are located in the dermis, as a heterogeneous cell population, including specific CD11b+, CD103+, and CD301b+ cell subsets.^51,52 dDCs actively migrate in the dermis to monitor the surrounding environment. They are important components of steady-state tolerance, immune regulation during skin injury, and the initial T cell response to skin pathogens⁵³ (Figure 1). In mice skin, γδ T cells account for 50% of the total T cells. These cells constitutively express IL-23 receptors, CCR6, and RORγt. Under IL-23 or IL-1β stimulation, γδ T cells produce IL-17A, promoting neutrophil recruitment.⁵³ ILCs are a heterogeneous cell population with diversity in cytokine production, effector functions, and tissue location. ILCs do not express TCR or BCR but share characteristics with lymphocytes.⁵⁴ According to their developmental requirements, expression of cytokines, and cell surface markers, ILCs are divided into three groups: ILC1s, ILC2s, and ILC3s. Under normal physiological conditions, the skin contains three subsets of ILCs.^54,55 Recent research has discovered a pathway initiated by cold-sensing neurons, which activates skin ILC2s to maintain skin thermal homeostasis. Studies in mouse animal models have identified that cold-sensing nerves initiate a specific signaling cascade to activate cutaneous ILC2s. Upon stimulation of the transient receptor potential melastatin 8 (TRPM8) cold receptors expressed in skin sensory neurons, IL-18 is released, which in turn activates ILC2s to secrete IL-13 and IL-5, thereby inducing adipocyte browning and thermogenesis. This signaling axis uncovers the neuroimmune mechanisms governing cutaneous ILC2 activation.³⁹

Figure 1.

Schematic diagram of neuroimmune crosstalk within the skin barrier. Sensory nerve fibers in the epidermis and dermis of the skin secrete signaling molecules such as neuropeptides and neurotrophic factors, mediating bidirectional communication with tissue-resident immune cells including keratinocytes, Langerhans cells, macrophages, mast cells, dendritic cells and γδ T cells. Cutaneous sensory signals are transmitted to the spinal cord and central nervous system through the dorsal root ganglia and trigeminal ganglia, constituting a peripheral neuroimmune network for maintaining skin homeostasis. (Original schematic created with BioRender.com).

The Interaction and Regulatory Mechanisms of Neuro-Immunity During the Development of Skin Inflammation

Inflammation is caused by infection or abnormal immune reactions. According to the characteristics of immune cells and immune mediators, the immune response is mainly divided into type 1, type 2, and type 3. Type 1 immunity is mediated by adaptive helper T cells (Th1 cells), cytotoxic T cells, ILC1s, and natural killer cells, which secrete interferon gamma (IFN-γ) to combat intracellular pathogens and tumor cells. Adaptive Th2 cells, eosinophils, basophils, ILC2s, and mast cells mediate Th2-type responses by producing type 2 effector cytokines such as IL-4, IL-5, and IL-13. Type 3 immune responses are mediated by adaptive Th17 cells, γδ T cells, ILC3s, and neutrophils, producing IL-17 and IL-22 to combat extracellular bacteria and fungi.^56,57 There is increasing evidence indicating that immune cells in the skin can release various cytokines that directly act on cutaneous nerve endings. Simultaneously, the skin PNS perceives stimuli and transmits information to the CNS or nearby efferent neurons, leading to various neurological symptoms such as itching and pain.⁵⁸ The relationship between dermal mast cells and the nervous system is especially close during the development of inflammation. Neuropeptide SP released by sensory nerve endings induces mast cell degranulation and the release of inflammatory mediators such as histamine, mediating pro-inflammatory effects. Conversely, histamine released by mast cells induces the release of neuropeptides, which act on histamine receptors on sensory nerve endings, establishing a bidirectional loop between mast cells and sensory nerves.^59–61 Additionally, SP can induce mast cells to release VEGF, promoting endothelial cell proliferation and vascularization, thus exacerbating inflammatory symptoms.^36,39,45 In acute skin inflammation, neuropeptides and neurotrophic factors lead to inflammation by upregulating the expression of SP, NGF, and IFN-γ, and subsequently contribute to fibrosis in chronic skin inflammation.^5,62–67

The Neuroimmune Mechanisms of Specific Inflammatory Skin Diseases

AD

AD is a common chronic relapsing inflammatory skin disease with a significant disease burden. Dysregulation of the neuroimmune circuitry plays a key role in the pathophysiology of AD, including inflammation, itching, pain, and barrier dysfunction.⁶⁸ Sensory nerves can be activated by environmental or endogenous triggers, transmitting itching stimuli to the brain. Upon stimulation, sensory nerve endings can release neuro-mediators into the skin, triggering inflammation, barrier dysfunction, and itching.⁶⁹ Furthermore, dysfunction of CNS and PNS structures can lead to neuro-inflammation, sensitization, nerve elongation, and neuropathic itching, resulting in chronic inflammation and treatment resistance.⁷⁰ Itching is a common feature among all phenotypes, acute severity, and severity levels of AD, indicating the crucial role of sensory nerves in AD^69,71,72 (Figure 2B). Endogenous or exogenous triggers of AD (such as protons, allergens, microbes, irritants, or antigens) can directly or indirectly activate high-affinity receptors on peripheral sensory nerve endings [such as transient receptor potential (TRP) ion channels, toll-like receptors (TLRs), and protease-activated receptors (PARs)] through epidermal cells and immune cells. Peripheral sensory nerves release neurotransmitters, stimulating signals from the central primary sensory nerve endings to the spinal dorsal horn, ultimately resulting in scratching or withdrawal reflexes^68,73–75 (Figure 2C).

Figure 2.

Mechanisms and triggers of atopic dermatitis (AD). (A) Involvement of multiple immune cells and cytokines in AD pathogenesis. Skin-resident dendritic cells and keratinocytes recruit B cells, eosinophils, and T cells to lesional skin via release of TSLP, CTLA-4, and other mediators. Among T-cell-mediated responses, the Th2-type predominates in AD. (Reproduced from.⁷⁶ Copyright © 2024 by the authors, licensed under CC BY 4.0) (B) Neuroimmune crosstalk underlying chronic non‑histaminergic pruritus in AD. Keratinocytes, Th2 cytokines, various immune cells, and cutaneous unmyelinated C‑fibers form an interactive network. Pruritic signal transduction is mediated by PAR2, TRP channels, MRGPR family members, cytokine receptors, and the downstream JAK/STAT signaling axis. (Reproduced with permission⁷² from Copyright © 2024, Elsevier Inc) (C) Factors influencing inflammation and epidermal barrier disruption in AD. Genetic susceptibility, environmental factors, allergens, and irritants trigger immune dysregulation and impair barrier function. Reduced antimicrobial peptides, altered pH, type 2 cytokine release (TSLP, IL‑4, IL‑13, IL‑31, IL‑33) during the itch–scratch cycle, and Th2 inflammation further perpetuate the vicious cycle. In addition, AD may be accompanied by multisystem comorbidities. (Reproduced with permission from⁶⁸ Copyright © 2025, Elsevier Ltd).

AD patients’ skin lesions contain various immune cells, including mast cells, eosinophils, basophils, ILC2s and DCs.³⁵ After IgE binds to FcεRI on mast cells and recognizes antigens, mast cells release various effector molecules such as histamine, serotonin, proteases, and various cytokines, which can activate sensory neurons and cause itching sensation.^38,77 Activated sensory neurons release neuropeptides or neurotransmitters that act on mast cells, forming a neuroimmune feedback loop. Mast cells express various neuropeptide receptors such as SP receptors, CGRP receptors, NPY receptors, and VIP receptors.⁷⁸ In addition, animal studies have demonstrated that mast cells can secrete NGF, and binding of NGF to TrkA tyrosine receptors on mast cells induces cellular degranulation.⁷⁹ Human mast cells express Mas-related G protein-coupled receptor X2 (MRGPRX2). Binding of cationic molecules including neuropeptides and host defense peptides to this receptor promotes mast cell degranulation and trypsin release.⁸⁰ Since tryptase is also an itch inducer, it suggests the existence of heterogeneous neuroimmune pathways in innate immunity. Mast cells increase at AD lesion sites in patients and mouse models and exhibit degranulation, but the mechanisms remain unclear.⁸¹ Possible mechanisms include: when mast cells are activated by MRGPRX2 release inflammatory cell contents acting on sensory neurons, the sensory nerve fibers release neuropeptides via MRGPRX2 to promote mast cell activity,⁸² similar to previous findings where vanilloid 1+ neurons release SP to activate mast cells, and SP binding to mouse mast cell MRGPRB2 induces mast cell degranulation.^83,84 Accordingly, neuropeptides can interact with corresponding receptors at the interface between mast cells and sensory nerves. This process may facilitate mast cell degranulation and partly contribute to the pathogenesis of AD.

Eosinophils are similarly activated through IgE mediation, leading to degranulation and releasing various pre-stored intracellular effector molecules such as histamine, leukotrienes, cytokines IL-4, and IL-13.⁸⁵ Among them, the interaction between type 2 cytokines and sensory neurons is a key mechanism of chronic itching in AD.⁸⁶ IL-4 and IL-13 can directly activate sensory neurons in both mice and humans, and the release of IL-4 and IL-13 by eosinophils plays an important role in chronic itching in AD.⁸⁷ Sensory neurons express leukotriene receptor CysLTR2,⁸⁸ indicating that the interaction between eosinophils and neurons can induce itching. Additionally, functional MRGPRX2 is also highly expressed in eosinophils.^89,90

DCs possess unique functions in antigen uptake and presentation. In the lesions of AD patients, inflammatory epidermal DCs (CD11c+CD206+) are distributed in the central zone of spongiotic epidermis. These DCs can induce T cell responses, providing potential targets for treatment.^91,92 Direct injection of papain into the skin of mice promotes the migration of CD301b+ DCs from the skin to draining lymph nodes and initiates Th2 cell differentiation by binding SP to the surface receptor MRGPRA1 on DCs.⁹³ NPY induces the migration of immature DCs derived from human monocytes and promotes Th2 polarization by binding to the NPY Y1 receptor in vitro.⁹⁴ In contrast to NPY, the effects of VIP on DCs are multifaceted. In vivo and in vitro experiments have found that VIP treatment promotes high expression of CD86 in immature DCs, which can promote CD4+ T cell proliferation and tend toward a Th2 phenotype. However, VIP can reduce the expression of CD86 and CD80 on the surface of DCs when stimulated with lipopolysaccharide (LPS), then inhibit T cell proliferation.⁹⁴ The above findings indicate that VIP exerts distinct effects, which may be determined by whether the host is under infectious or stimulatory conditions. SP transmits itching signals in the nervous system. Studies on human skin have found that IL-31 can activate sensory neurons to release SP, which stimulates DCs to secrete inflammatory factors and forms a neuroinflammatory positive feedback loop that mediates pruritus signal transduction in AD.^95,96

ILC2s play important roles in various tissues, expressing specific receptors that can be activated by epithelial-derived cytokines such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP).⁹⁷ In addition, existing studies have demonstrated that the above cytokines also exert critical roles in AD by regulating keratinocyte activity and the integrity of the skin barrier⁷⁶ (Figure 2A). In skin lesions of AD patients, the expression of IL-33, IL-25, and TSLP is upregulated, indicating the involvement of ILC2s in AD.⁹⁸ ILC2s significantly accumulate in the skin lesions of AD patients, particularly in the inflamed dermis, where they are distributed around eosinophils. In AD mouse models, eosinophils secrete IL-4 to promote ILC2 activation, leading to subsequent secretion of IL-5 and IL-13 by ILC2s in skin, exacerbating AD skin inflammation.^99,100 Therefore, in AD, skin ILC2s promote type 2 skin inflammation and interact synergistically with other innate immune cells.¹⁰¹ However, the specific mechanism of interaction between ILC2s and neurons in AD has not been elucidated and requires further investigation.

Psoriasis

Psoriasis is a neurogenic skin inflammation characterized by dysregulation of the IL-17/IL-23 axis, epidermal hyperplasia, excessive keratinization, and itching, where neuroimmune interactions mediate IL-23 signaling to induce inflammatory lesions^79,102,103 (Figure 3A). Abnormal Th1/Th17-type immune responses are the main cause of psoriasis, wherein cytokines such as IFN-γ, IL-17A, IL-23, and TNF-α lead to proliferation of keratinocytes and persistent skin inflammation^104,105 (Figure 3B). In psoriatic lesions, there is an increase in SP, CGRP, and VIP-positive nerve fibers.⁵ Compared with normal human skin, morphological contacts between neurofilament-positive neurons and tryptase-positive mast cells are more abundant in psoriatic lesions, indicating mast cell-neuron crosstalk within lesional tissue.⁵⁹

Figure 3.

Neuroimmune mechanisms in psoriasis. (A) Th1/Th17 inflammation‑associated neuro-innate immune crosstalk in psoriasis. Genetic predisposition, environmental triggers, and psychological stress modulate the skin microenvironment. Type 1 and type 17 cytokines promote keratinocyte proliferation and sustain cutaneous inflammation. Concurrently, sensory nerves release neuropeptides including SP, CGRP, VIP, and galanin, which recruit and activate mast cells, neutrophils, dendritic cells, ILC3s, and other immune cells that also participate in maintaining skin inflammation. (Reproduced from.⁷⁹ Copyright © 2023 by the authors, licensed under CC BY 4.0) (B) Interplay among sensory neurons, keratinocytes, and immune cells during psoriasis pathogenesis. Allergens, pathogens, and mechanical injury stimulate sensory neurons, leading to release of SP, CGRP, NPY, and other neuropeptides, which in turn promote mast cell degranulation and dendritic cell activation. Activated dendritic cells induce Th17 cell differentiation and secretion of IL‑17 and IL‑22, ultimately recruiting neutrophils to sustain epidermal hyperproliferation and drive neurogenic inflammation. (Reproduced with permission from¹⁰⁵ Copyright © 2025, Elsevier Ltd) (C) Molecular pathways of CGRP and SP in psoriasis. Under external stress, TRPV1 and TRPA1 ion channels are activated, resulting in release of CGRP and SP. These neuropeptides act on dendritic cells to promote secretion of IL‑23 and IL‑12, thereby triggering immune dysregulation. (Reproduced from¹⁰⁶ Copyright © 2023 by the authors, licensed under CC BY-NC 3.0).

Psoriasis patients exhibit elevated plasma levels of CGRP, and CGRP receptors are detected in psoriatic lesions. Studies revealed that SP and CGRP induce mast cells to release various cytokines such as IL-1β and TNF-α, subsequently recruiting neutrophils to psoriatic lesions. Neutrophils produce antimicrobial peptides like α-defensins, leading to sustained inflammatory reactions.^107,108 Meanwhile, SP can also facilitate the transcriptional activation of pro-inflammatory cytokines in dendritic cells¹⁰⁹ (Figure 3C). In addition to SP and CGRP, galanin is another biologically active neuropeptide, vascular endothelial cells express its receptor galanin-R3.¹¹⁰ In a mouse model of psoriasis induced by imiquimod, knocking out galanin-R3 can alleviate disease phenotypes, including inhibiting angiogenesis, neutrophil infiltration, and pro-inflammatory cytokine secretion.¹¹¹ Furthermore, the expression of NGF and its receptor TrkA is also increased in psoriatic lesions.^112,113 These findings suggest that the nervous system may contribute to the skin inflammation in psoriasis. In addition to neuropeptides, DCs and innate lymphocytes, especially ILC3, also play important roles in the skin inflammation of psoriasis. Similarly, in a mouse model of psoriasis induced by imiquimod, it was found that activation of transient receptor potential V1+ (TRPV1+) neurons at psoriatic lesions promotes dDCs to secrete IL-23, which in turn stimulates dermal γδ T cells to secrete IL-17A, IL-17F, and IL-22. This leads to excessive proliferation of keratinocytes and recruitment of more neutrophils to the lesion site, resulting in exacerbating skin inflammation in psoriasis.¹⁰² Th17 cells represent the predominant adaptive T cell subset within Type 3 immunity. ILC3s can produce type 3 cytokines IL-17A and IL-22, playing an important role in the occurrence and development of psoriasis.^114,115 NCR+ILC3s increase in psoriatic lesions, and after stimulation with IL-23 and IL-1β, ILC3s isolated from psoriatic lesions can produce IL-22 in vitro.¹¹⁶ Currently, research on the regulation of ILC3s by neurons in the context of psoriasis is not yet well understood and requires further investigation. In vivo and in vitro mouse models, we found that LCs can secrete IL-23, and activated DCs secrete inflammatory cytokines such as IL-12 and IL-23. At the same time, CGRP promotes the infiltration of DCs and T cells into psoriatic lesions,¹¹⁷ while VIP can promote LCs to present antigens and secrete pro-inflammatory cytokines such as IL-17A and IL-6.¹¹⁸

Neuroimmune Regulation and Its Mechanisms in Other Types of Dermatitis Inflammation

In rosacea, neuropeptides such as Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP), SP, VIP, and CGRP are present at higher levels than in normal skin tissue.⁵ In experimental studies at the human level, we found that PACAP can stimulate endothelial cells to release nitric oxide (NO) and also act directly on arterial smooth muscle cells, thereby exerting vasodilatory effects either indirectly or directly.^119,120 Whereas SP plays a key role in edema formation in postcapillary venules of rosacea via NK1 receptors,^121,122 VIP¹²³ and CGRP¹²⁴ act as potent vasodilators by acting on smooth muscle cells in arterioles. Clinical observations indicate that neuropeptides also activate mast cells to release histamine, induce vasodilation, and release tryptase, thereby promoting fibrosis in rosacea.^125,126 In addition, based on clinical biopsy findings and animal experiments, it is hypothesized that in rosacea, neuropeptides upregulate vascular cell adhesion molecule (VCAM) to stimulate the production of IL-1β, subsequently activating leukocyte migration.⁵ Besides neuropeptides, sensory nerves expressing Toll-like receptor 2 (TLR2) and protease-activated receptor 2 (PAR2) also play a critical role in the inflammation of rosacea.¹²⁷ Activation of TLR2 can promote the expression and release of prostaglandin E2, TNF-α, IL-1β, as well as various other proangiogenic factors, cytokines, proteases, and chemokines. In addition, the LL37 signaling pathway exerts a crucial function in the pathogenesis of rosacea¹²⁸ (Figure 4A). Aberrant activation of the TLR2/KLK5/LL37 cascade is recognized as one of the potential pathogenic mechanisms underlying this disease¹²⁹ (Figure 4C), which indirectly indicates a close correlation between TLR receptors and rosacea; stimulation of PAR2 can induce pain, pruritus, and inflammation. The activation and expression of these two receptors exacerbate the dysregulation of neurovascular modulation to a certain extent^129–131 (Figure 4B).

Figure 4.

Neuroimmune Regulation in Rosacea. (A) Role of LL-37 in the pathogenesis of rosacea. LL-37 interacts with key molecules including TLR2, mTORC1, CXCL8, and MRGPRX2, activating macrophages, neutrophils, T cells, mast cells, and plasmacytoid dendritic cells, leading to production of multiple cytokines that contribute to inflammatory responses, immune modulation, and angiogenesis in rosacea. (Reproduced from¹²⁸ Copyright © 2024 by the authors, licensed under CC BY 4.0) (B) Complex interplay among nerves, blood vessels, and immune cells during rosacea pathogenesis. External stimuli activate TRPV-positive sensory neurons to secrete neuropeptides, which activate mast cells via MRGPRX2 to release vasoactive and pro-inflammatory mediators. In turn, immune products reciprocally sensitize nerves, simultaneously inducing vascular abnormalities, collectively mediating pain and pruritus in rosacea. (Reproduced from¹²⁹ Copyright © 2023 by the authors, licensed under CC BY 4.0) (C) Schematic of the TLR2/KLK5 pathway. External stimuli upregulate TLR expression, activate mTORC1 signaling, and promote KLK5 production. KLK5 cleaves hCAP18 to generate active LL-37. LL-37 further activates NF-κB the NLRP3 inflammasome, and the JAK/STAT pathways, resulting in massive release of pro-inflammatory mediators. Neutrophils and mast cells secrete MMP9 to activate pro-KLK5, establishing a positive feedback loop that sustains and amplifies inflammation. The AhR bidirectionally regulates this pathway to restrain excessive inflammatory activation. (Reproduced from¹²⁹ Copyright © 2023 by the authors, licensed under CC BY 4.0).

In prurigo nodularis (PN), NGF and CGRP are the main neuro-mediators involved in these processes.^132,133 In PN skin lesions, the number of CGRP+ nerve fibers increases in the dermis and co-localizes with mast cells and eosinophils.¹³⁴ Mast cells and eosinophils are also increased in PN lesions compared to normal skin but are absent in areas without nerve fibers¹³⁵ (Figure 5A). This may indicate reciprocal crosstalk between them. The interaction between neuropeptide CGRP and skin immune cells such as mast cells or eosinophils is involved in the pathogenesis of PN.¹³⁴ CGRP and SP promote the chemotaxis, activation, and survival of eosinophils together.^136,137 Eosinophils can produce NGF, a neurotrophic factor that promotes neuropeptide release and also has direct or indirect pro-inflammatory effects. NGF can activate eosinophils to release pro-inflammatory mediators.¹³⁸ In vivo and in vitro animal experiments, NGF may activate TrkA receptors, upregulate the expression of TRPV1 on nerve fibers, followed by the release of SP and CGRP, thereby forming a bidirectional neuroimmune feedback loop.¹³⁹ In addition, the neuro-cutaneous anatomical alterations induced by the aforementioned immune inflammation can trigger severe pruritus, pain and other paresthesias, which further facilitate the formation of hyperkeratotic and fibrotic nodules in PN¹⁴⁰ (Figure 5B).

Figure 5.

The Role and Mechanism of Neuroimmunity in Prurigo Nodularis (PN). (A) Interactions among immune cells, inflammatory cells, and nerve fibers in PN. Keratinocytes secrete growth factors and pro-inflammatory cytokines to activate local immunity and recruit infiltrating Th2 cells, eosinophils, and mast cells, thereby inducing cutaneous inflammation and epidermal hyperplasia. Concurrently, dermal nerve hyperplasia releases SP, CGRP, and other neuropeptides that stimulate immune cells and keratinocytes, further amplifying inflammatory signals. In addition, repeated scratching can damage epidermal nerve endings. (Reproduced from¹³⁵ Copyright © 2024 by the authors, licensed under CC BY 4.0) (B) Neuroimmune interactions in the itch-scratch cycle. Infiltrating inflammatory cells, inflammatory mediators, and neuropeptides drive inflammatory responses in the dermis. Repeated scratching stimulates epithelial cells to secrete IL-33 and TSLP, thereby exacerbating local neuroimmune dysregulation. (Reproduced from¹⁴⁰ Copyright © 2025 by the authors, licensed under CC BY 4.0).

Neuroimmune Interactions During Intestinal Infections

The human intestine is directly connected to the external environment and exposed to microbial stimuli constantly. Consequently, the immune system of the intestines plays a crucial role in defending the body against external microorganisms.¹⁴¹ Dense nerves innervate the intestines. In addition to the spinal dorsal root nerves, vagus nerve, and sympathetic nerves, which are directly connected to the CNS, the intestines also possess a unique intrinsic nervous system. The former with the gut microbiota constitutes the gut-brain axis.¹¹ The latter, entirely located within the intestines, exerts distinctive neuroimmune regulatory functions.¹⁴² The following sections will introduce the neuroimmune of intestinal inflammation from the perspectives of spinal DRG, the vagus nerve, the sympathetic nervous system, and the enteric intrinsic nervous system.

DRG Neurons

Research indicates that neural impulses derived from organs can enter the spinal cord via DRG neurons, forming synapses either in the dorsal horn of the spinal cord or continuing upward to the brainstem. This pathway is closely linked to the perception of intestinal pain¹⁴³ (Figure 6A). First, after receiving stimuli, these neurons can produce neurotransmitters such as CGRP, tachykinins, NO, SP, and cholecystokinin.¹² These neurotransmitters bind to their corresponding receptors to exert immunomodulatory effects. For instance, in vivo and in vitro animal experiments, stimulation of TLR4 on the neuronal surface by LPS from Gram-negative bacteria can activate Transient Receptor Potential Cation Channel Subfamily V Member 1 (TRPV1), trigger CGRP release, downregulate TNF-α levels, and cooperate with macrophages and DCs to regulate immune responses.¹⁴⁴ This suggests that neuronal surface receptors may become activated under infectious inflammatory conditions. Moreover, intestinal nociceptors can detect pathogenic bacteria in the gut and initiate corresponding immune responses. Intestinal microfold cells (M cells) serve as an entry route for Salmonella invasion. TRPV1 and Nav1.8-positive nociceptor neurons in the intestine can downregulate intestinal M cell levels via CGRP, thereby inhibiting Salmonella invasion and playing an immune defense role.¹⁴⁵ Studies have shown that TRPV1-negative mice have less IL-22 and T cell recruitment in the colon during bacterial colitis than TRPV1-positive mice, indicating that TRPV1 assists the immune system in clearing pathogens.¹⁴⁶ Furthermore, intestinal nociceptors can also maintain the level of segmented filamentous bacteria (SFB) in the small intestine, which can resist Salmonella infection.¹⁴⁵

Figure 6.

Neuroimmune Interactions among Spinal Dorsal Root Nerves (DRG), Vagus Nerves, and Sympathetic Nerves during Intestinal Infection. (A) Involvement of DRG in gut pain sensation. Neural impulses from the gut enter the spinal cord via DRG and form synapses in the dorsal horn or ascend to the brainstem, thereby contributing to the generation of visceral pain. (B) Connections of the vagus nerve. Vagal efferents project to the dorsal motor nucleus and the nucleus tractus solitarius, where they collect and integrate visceral sensory information. (C) Efferent signaling pathways of the sympathetic nervous system. The central nervous system releases acetylcholine to regulate sympathetic ganglia and the adrenal medulla, promoting catecholamine release, which subsequently acts on gut tissues. (D) Integrated neuroimmune network in intestinal inflammation. DRG, upon stimulation, produce mediators such as CGRP, SP, and tachykinins that participate in immune regulation. The vagus nerve can suppress inflammation either by inhibiting the release of pro-inflammatory cytokines (TNF, IL-1β, IL-6, IL-18) or via the cholinergic anti-inflammatory pathway through ACh release. Norepinephrine released by sympathetic nerves exerts anti-inflammatory effects by reducing lymphocyte numbers and inhibiting T-cell activation. (Original schematic created with BioRender.com).

Vagus Nerve (VN)

The VN is the only cranial nerve that innervates thoracoabdominal sensation, composed of 80% afferent and 20% efferent fibers,¹³ playing a crucial role in neuroimmune interactions during intestinal infection.¹⁴⁷ VN afferent fibers originate from various intestinal layers and converge in the solitary nucleus (NTS). VN efferent branches connect to the dorsal motor nucleus and NTS, serving as the site for collecting and integrating visceral sensory information¹³ (Figure 6B). Research by Toshiaki Teratani et al found that the hepatic vagal afferent branches can sense the gut microenvironment, forming a liver-gut-brain circuit. Sectioning this pathway reduces peripheral regulatory T (pTreg) cell numbers and increases susceptibility to colitis.¹⁵ This effect may be related to the expression of aldehyde dehydrogenase (ALDH) in gut antigen-presenting cells and the reduction in retinoic acid synthesis.¹⁵ This study demonstrates that the liver-brain-gut reflex arc regulates the number of pTreg cells and maintains intestinal homeostasis, providing new insights for the treatment of diseases such as IBD.¹⁵

In animal experiments, it was found that stimulating VN can inhibit the release of inflammatory cytokines (eg, TNF, IL-1β, IL-6, IL-18),¹⁴⁸ thereby exerting anti-inflammatory effects.¹⁴⁹ In IBD, cytokines such as TNF-α and IL-6 bind to vagal receptors and activate the hypothalamic-pituitary-adrenal (HPA) axis to release glucocorticoids (GC), which suppress inflammation. Vagal afferent nerves can also transmit information to efferent nerves, releasing ACh to activate the CAIP and exert its anti-inflammatory effects. ACh binds to nicotinic acetylcholine receptors (nAChRs) on macrophages, achieving anti-inflammatory effects^13,14 by inhibiting intestinal macrophages activation,¹⁵⁰ suppressing macrophages inflammatory cytokines secretion,¹⁵¹ and modulating the spleen-macrophage pathway.¹⁵² Numerous studies have confirmed the relationship between VN and macrophages, demonstrating that stimulating VN effectively inhibits macrophage activation.^153–158 Furthermore, research has shown that the VN interacts with mast cells via substances such as ACh, thereby reducing inflammation and maintaining intestinal mucosal integrity.¹⁵⁹ External stimuli and cytokines can activate the VN. Under such conditions, this nerve mainly suppresses the initiation and progression of inflammation.

Sympathetic Nervous System

The sympathetic nervous system regulates intestinal immunity by secreting catecholamines (eg, NE, epinephrine, and dopamine)¹⁶⁰ (Figure 6C). NE binds to NE receptors on immune cells then exerts broad immunosuppressive effects. Studies have shown that NE can reduce lymphocyte numbers,¹⁶¹ limit CD4+ T‑cell proliferation,¹⁶² and inhibit T‑cell activation by suppressing antigen‑presenting cell (APC) function,¹⁶³ thereby exerting important anti-inflammatory effects. These anti‑inflammatory effects are closely associated with both the glucocorticoid receptor (GCR) and the β₂‑adrenergic receptor (β₂‑AR). Additionally, partial sympathetic neurons can express tyrosine hydroxylase (TH), which is important for gut immunity. TH‑positive neurons can promote the resident muscularis macrophages (MMs) transforming into an anti‑inflammatory M2 macrophages via β₂‑AR, thereby resisting inflammation¹⁶⁴ (Figure 6D).

ENS Immunity

ENS is an intrinsic intestinal neural network derived from the neural crest, primarily from the vagal level of the neural axis.¹⁶⁵ Composed of more than 50 billion neurons and glial cells distributed in the intestinal muscular and submucosal layers. The ENS contacts almost all intestinal cell and dominates the functions of intestinal motility, secretion, immunity, and blood flow.¹⁶⁶ Neuroimmune functions of the ENS are mainly mediated by intestinal motor neurons, intestinal endogenous primary afferent neurons, and intestinal glial cells. ENS neurons secrete various immunomodulatory substances, such as ACh, NE, NO, SP, and VIP, to regulate intestinal immunity. Experiments in mice conducted by Schneider et al confirm that the ENS can mediate chronic stress signals and exacerbate intestinal inflammation.¹⁶⁷ After sensing stress, the CNS elevates peripheral glucocorticoid levels, thereby driving the production of inflammatory subpopulations of intestinal glial cells and secretes macrophage colony-stimulating factor (M-CSF/CSF1) to further stimulate monocytes/macrophages and aggravate ulcerative colitis (UC). Simultaneously, glucocorticoid-induced transcriptional changes in neurons reduce mature neuron numbers and lower ACh levels, thus inducing colitis.¹⁶⁷

The latest research shows the ENS’s significant role in intestinal immunity. IL‑18 produced by muscle layer intestinal neurons in ENS can directly kill pathogens or stimulate goblet cells to produce antimicrobial proteins (AMPs), protecting against Salmonella typhi infection.¹⁶⁸ In addition, the intestinal neuroimmune pathway regulates innate immune cells at the intestinal barrier layer, thereby influencing IBD.¹⁶⁹ This effect may be related to intestinal microbiota, Paneth cells, neutrophils, macrophages, mast cells, eosinophils, and their secreted bioactive molecules.¹⁶⁹

Intestinal Motor Neuron

Some intestinal motor neurons regulate immune function by secreting neuropeptides such as VIP and NPY. Animal studies show that VIP secretion by VIP-positive neurons can regulate lymphocytes¹⁷⁰ and mononuclear phagocytes (MNPs)¹⁷¹ and regulate its’ secretion of cytokines, shifting immunity toward the Th2‑biased response. Research by Jhimmy Talbot et al indicates that VIP binds to receptors on ILC3s, inhibiting their secretion of IL‑22 and thereby influencing intestinal nutrient absorption and metabolism.¹⁷⁰ In turn, intestinal nutrient absorption can modulate systemic immune function. VIP‑ergic neurons in the ENS regulate MNPs activity via secreting VIP and its binding to vasoactive intestinal peptide receptor 1 (VPAC1) on CX3CR1⁺ MNPs¹⁷¹ (Figure 7A). In colitis mouse models, NPY-positive neuron numbers are upregulated, leading to increased intestinal permeability and aggravated inflammation.¹⁷² Furthermore, intestinal motor neurons activity affects mast cells function to regulate immunity. Mast cells co‑cultured with these neurons exhibit enhanced degranulation and release more neuromodulatory substances.¹⁷³

Figure 7.

Neuroimmune Interactions among Intestinal Motor Neurons, Intrinsic Primary Afferent Neurons (IPANs), and Enteric Glial Cells (EGCs). (A) Neuroimmune roles of enteric motor neurons. VIP-positive enteric motor neurons secrete VIP, which binds to receptors on ILC3s and CX3CR1⁺MNPs, thereby suppressing IL-22 secretion and modulating MNP functions. (B) Neuroimmune roles of IPANs in the gut. Bacteria stimulate enteric IPANs to transmit signals to immune cells, promoting immune system activation. In addition, IPANs secrete neuromedin U to activate ILC2s, contributing to anti-parasitic immunity. (C) Neuroimmune roles of EGCs. IL-1β and low-concentration IL-10 inhibit EGC proliferation. EGCs modulate macrophage phenotypes via connexin-43 (Cx-43), thereby influencing colitis and abdominal pain. Moreover, EGC-derived GDNF exerts anti-inflammatory effects through anti-apoptotic activity and inhibition of mast cell degranulation. (Original schematic created with BioRender.com).

Intrinsic Primary Afferent Neurons (IPANs)

The sensory neurons on the intestinal wall, which do not have complex neural pathways and are mostly not directly connected to the CNS or PNS, often referred to as IPANs. IPANs play a crucial role in immunomodulation and are of great significance for intestinal mucosal function, immune cell activation, and migration.¹⁷⁴ Mechanistically, gut bacteria can stimulate IPANs, and then relay signals to nearby immune cells, triggering an activation of the immune system against bacterial invasion.¹⁷⁵ Additionally, it is found in animal experiments that when stimulated by certain intestinal worms, IPANs can secrete neuromedin U (NMU). NMU binds to the corresponding receptor neuromedin U receptor 1 (NMUR1), and directly activating ILC2s to promote anti-parasitic immunity.^176,177 This mechanism is also related to the pathogenesis of IBD¹⁷⁸ (Figure 7B).

Enteric Glial Cells (EGCs) Immunity

The EGC network system is a supportive component of ENS, distributed throughout the intestine. It provides support to intestinal neurons, transmitting neurotransmitters, and processing relevant neuroimmune information.¹⁷⁹ EGCs are closely connected with intestinal immunity, homeostasis, tissue repair, and tissue regeneration.^180–182 Functionally, in vivo and in vitro mouse experiments, it was found that EGCs can regulate macrophage phenotypes and visceral sensitivity via connexin-43 (Cx-43), thereby influencing colitis and associated abdominal pain, etc.¹⁸³ They also secrete glial cell line-derived neurotrophic factor (GDNF), which exhibits potent anti-apoptotic activity, inhibits mast cell degranulation, and exerts anti-inflammatory effects.^184,185 However, excessive EGCs proliferation may lead to immune cell overactivation, thereby occurring or exacerbating inflammation.¹⁸⁶ Pro-inflammatory cytokines such as IL-1β or low concentrations of IL-10 can inhibit EGCs proliferation. IL-1β also regulates glial cells’ secretory function by enhancing IL-6 synthesis and secretion¹⁸⁷ (Figure 7C). EGCs may be one of the sources of intestinal IL-7, which protects T cells and may contribute to the occurrence and development of chronic intestinal inflammation.¹⁸⁸ Recent studies have shown that berberine can regulate enteric glial cells-intestinal epithelial cells-immune cells interactions, restore mucosal barrier homeostasis, regulate intestinal neurogenic inflammation, and exert protective effects against UC.¹⁸⁹

Treatment Targeting Neuroimmune Interactions in Inflammatory Skin and Intestinal Diseases

Given the central role of neuroimmune interactions in the pathogenesis of inflammatory skin and intestinal diseases, therapeutic strategies aimed at modulating this interaction have gained significant attention (Table 1). These approaches can be broadly categorized into pharmacological agents that target specific neuroimmune pathways and non-pharmacologic interventions. The specific drug classes involved in the former include biologics, small-molecule inhibitors and neuromodulatory drugs, while the latter involves specific non-pharmacologic interventions covering VN stimulation, peripheral focused ultrasound stimulation, and acupuncture. The following sections will elaborate on these two approaches.

Table 1.

Therapeutic Strategies Targeting Neuroimmune Interactions in Inflammatory Skin and Intestinal Diseases

Category	Agent/Therapy	Primary Mechanism/Target	Clinical Application/Level of Evidence	Key Notes	References
Biologics	Infliximab/Adalimumab	Anti-TNF-α monoclonal antibodies	Approved for psoriasis, psoriatic arthritis, and IBD (CD, UC)	First-line biologic for concurrent psoriasis and IBD.	[190,191]
	Etanercept	Soluble TNF-α receptor-Fc fusion protein	Approved for psoriasis; not recommended/may worsen IBD	Avoid in patients with concurrent IBD due to limited efficacy and possible exacerbation.	[192,193]
	Ustekinumab	Anti-IL-12/23p40 monoclonal antibody	Approved for moderate-to-severe psoriasis and CD	Preferable for patients with both skin and intestinal manifestations.	[194,195]
	Guselkumab/Risankizumab	Anti-IL-23p19 monoclonal antibodies	Approved for psoriasis; Phase III for CD (positive results)	More selective than ustekinumab, preserving IL-12-mediated Th1 immunity.	[196,197]
	Secukinumab / Ixekizumab	Anti-IL-17A monoclonal antibodies	Approved for psoriasis; contraindicated in active IBD or history of IBD	Blockade can impair the intestinal barrier, leading to new-onset or worsening IBD.	[198,199]
	Dupilumab	Anti-IL-4Rα monoclonal antibody	Approved for atopic dermatitis (AD)	Use with caution in patients with comorbid IBD.	[200–202]
	Nemolizumab	Anti-IL-31RA monoclonal antibody	Approved for AD (pruritus)	Reduces IL-31-mediated itch and neuropeptide release.	[200]
	Tralokinumab	Anti-IL-13 monoclonal antibody	Approved for AD	Blocks IL-13-induced sensory neuron activation.	[200]
Small-molecule inhibitors	Upadacitinib	JAK1 inhibitor	Approved for AD and IBD (UC, CD)	Rapid onset.	[203,204]
	Abrocitinib	JAK1 inhibitor	Approved for AD	Reversibly and selectively inhibits JAK1.	[205]
	INNA1605 (topical)	MyD88 inhibitor	Phase II for psoriasis and AD (Phase I completed)	First-in-class small-molecule MyD88 inhibitor.	[206,207]
Neuromodulatory drugs	Cannabinoids (eg, β-caryophyllene)	CB1/CB2 receptor agonists	Preclinical (AD, psoriasis, IBD models)	CB2-selective or peripherally restricted agents are under development to avoid CNS side effects.	[208–210]
	Asivatrep (PAC-14028)	TRPV1 antagonist (non-competitive)	Phase III for AD (completed); Preclinical for colitis	Well-tolerated; no significant hyperthermia reported, unlike earlier TRPV1 antagonists.	[211–213]
	α7nAChR agonists (eg, GTS-21, PNU-282987)	α7 nicotinic acetylcholine receptor agonists	Preclinical (colitis, psoriasis models)	Activate cholinergic anti-inflammatory pathway (CAIP).	[214–216]
	Central AChE inhibitors (eg, Galantamine, Rivastigmine)	Brain acetylcholinesterase inhibitors	Preclinical/experimental (IBD models)	Activate central muscarinic-VN-α7nAChR pathway; CNS side effects limit translation.	[217–220]
	mAChR agonists (eg, McN-A-343)	M1 muscarinic receptor agonists	Preclinical (colitis models)	Show anti-inflammatory effects in UC models; skin research remains early.	[221–223]
	β3-AR agonists (eg, Mirabegron)	β3-adrenoceptor agonists	Preclinical (colitis models); colon-targeted prodrugs show enhanced efficacy	Activates the Nrf2/HO-1 pathway; potential for IBD.	[224]
	β2-AR agonists (eg, Salmeterol)	β2-adrenoceptor agonists	Preclinical (psoriasis model)	Inhibits keratinocyte proliferation via cAMP/PKA.	[225]
	α2-AR agonists (eg, Brimonidine)	α2-adrenoceptor agonists	Approved for facial erythema in rosacea	Mainly vasoconstrictive; not primarily anti-inflammatory.	[226]
Non-pharmacological interventions	Invasive VNS (iVNS)	Surgical vagus nerve stimulation	Clinical studies (IBD, epilepsy, depression)	Effective but invasive; risk of surgical complications.	[227]
	Transcutaneous VNS (tVNS)	Non-invasive auricular/cervical VNS	Clinical studies (IBD)	Safer than iVNS; lack of large-scale RCTs hinders adoption.	[228–231]
	Peripheral focused ultrasound (pFUS)	Ultrasound-induced neuromodulation (splenic nerve)	Preclinical (DSS colitis)	Non-invasive; stimulates CAIP; technical challenges remain (parameter standardisation, targeting).	[232–235]
	Electroacupuncture/Manual acupuncture	Somato-autonomic reflex modulation	Clinical studies/meta-analyses (UC, IBD); limited evidence for skin diseases	Acupoint-specific effects; lack of standardised protocols; guidelines advise against in AD.	[236–241]

Biologics

Biologics are macromolecular drugs derived from living organisms or synthesized through biotechnological approaches. By virtue of their high specificity, they target key cytokines (eg, TNF-α, IL-4/13) or immune cell surface molecules (eg, CD20, IL-4Rα), thereby playing a significant role in modulating neuroimmune interactions.

TNF-α Inhibitors

TNF-α inhibitors were the first class of biologics to be used for the treatment of inflammatory skin and intestinal diseases, with representative agents including infliximab and adalimumab.^190,191 As a core inflammatory cytokine, TNF-α is highly expressed in both psoriatic skin lesions and intestinal inflammation in IBD; thus, targeting TNF-α can simultaneously suppress inflammatory responses in both the skin and the gut.^242,243 Both infliximab and adalimumab have been approved for the treatment of moderate-to-severe psoriasis, psoriatic arthritis, and IBD (including Crohn’s disease and ulcerative colitis). By neutralizing soluble and membrane-bound TNF-α, these antibodies inhibit downstream inflammatory cascades, indirectly reducing excessive keratinocyte proliferation in the skin and promoting mucosal healing in the intestine.^244,245 With regard to neuroimmune regulation, animal studies and in vitro experiments have demonstrated that TNF-α can upregulate the expression of NPY in enteric neurons; consequently, TNF-α inhibition may indirectly modulate intestinal barrier function and motility through neuropeptide-mediated pathways.^172,246 Therefore, for patients with concurrent psoriasis and IBD, TNF-α inhibitors are recommended as the first-line biologic choice.

However, not all TNF-α inhibitors are equally effective in the intestinal tract. Etanercept, which primarily neutralizes soluble TNF-α, has limited efficacy in IBD and may even exacerbate intestinal inflammation; therefore, it should be avoided in patients with concurrent IBD.^192,193 In addition, some patients may develop paradoxical psoriasiform skin lesions during anti-TNF-α therapy, in which case switching to alternative agents such as ustekinumab may be considered.²⁴⁷

IL-12/23 Inhibitors and IL-23 Inhibitors

The IL-23/IL-17 axis represents a shared core driver pathway in both psoriatic skin inflammation and intestinal mucosal inflammation in IBD.²⁴⁸ Ustekinumab, a fully human monoclonal antibody targeting the shared p40 subunit of IL-12 and IL-23, is approved for moderate-to-severe psoriasis and moderate-to-severe Crohn’s disease.¹⁹⁴ Its dual efficacy makes it a preferred option for patients with concurrent skin and intestinal manifestations. By simultaneously blocking the Th1 and Th17 pathways, ustekinumab effectively reduces psoriatic plaque formation and intestinal mucosal inflammation.¹⁹⁵ Newer IL-23p19 inhibitors, such as guselkumab and risankizumab, specifically target the p19 subunit unique to IL-23, thereby achieving more precise blockade while preserving IL-12-mediated Th1 immunity.¹⁹⁶ These agents have demonstrated efficacy superior or equivalent to ustekinumab in psoriasis and have shown promising results in phase III clinical trials for Crohn’s disease, with approvals already granted for active moderate-to-severe Crohn’s disease.^196,197

IL-17 Inhibitors

IL-17 inhibitors (eg, secukinumab and ixekizumab) demonstrate marked efficacy in moderate-to-severe psoriasis, achieving rapid and durable clearance of skin lesions through direct neutralization of IL-17A.¹⁹⁸ However, these agents are strictly contraindicated in patients with active IBD or a history of IBD. Although IL-17A is also elevated in intestinal inflammatory tissues, clinical trials and post-marketing surveillance consistently indicate that IL-17 blockade not only fails to ameliorate intestinal inflammation but may instead exacerbate or precipitate new-onset Crohn’s disease and ulcerative colitis.¹⁹⁹ The mechanistic basis for this paradoxical effect lies in the dual role of IL-17A in the gut: in contrast to its predominantly pro-inflammatory function in the skin, IL-17A in the intestine helps maintain intestinal epithelial barrier integrity by promoting the expression of tight junction proteins and antimicrobial peptides.²⁴⁹ Blockade of IL-17 signaling impairs this barrier, leading to microbial translocation and subsequent immune activation, thereby inducing or aggravating intestinal inflammation.²⁵⁰ Therefore, in patients with psoriasis and known IBD, IL-17 inhibitors should be strongly avoided, and alternative agents such as TNF-α inhibitors or ustekinumab should be prioritized.

Monoclonal Antibodies Targeting Key Mediators of Type 2 Inflammation

Type 2 inflammation, characterized by elevated levels of IL‑4, IL‑13, and IL‑31, represents the predominant immunological hallmark of AD and prurigo nodularis (PN), both of which exhibit significant neuroimmune dysregulation.⁸⁶ The sensory neurons release pro-inflammatory cytokines and neuropeptides, activating various immune cells and triggering an atopic response of the body. The IL4Rα-mediated signal transduction activated by the classic immune signaling pathway IL-4/IL-13, promotes itch activation through JAK signal transduction and transcriptional (JAK-STAT) activators in sensory neurons. This activation directly stimulates sensory neurons in mice and humans, thereby affecting the occurrence and development of chronic itch.²⁰⁰ Several monoclonal antibodies targeting IL-4 and IL-13 have been studied in clinical trials for AD. Some medications, such as nemolizumab (anti-IL-31RA), tralokinumab (anti-IL-13), and dupilumab (anti-IL-4Rα), can significantly alleviate itching in AD and have been approved for the treatment of AD.²⁰⁰

It should be emphasized that such biologics targeting type 2 inflammation are not indicated for the treatment of psoriasis or IBD, as the latter are driven by Th1/Th17‑type immunity rather than type 2 inflammation. Furthermore, case reports have suggested that agents such as dupilumab may induce or exacerbate IBD in susceptible individuals, a phenomenon possibly attributable to compensatory upregulation of the Th1/Th17 pathway following IL‑4/13 blockade.^201,202 Therefore, in patients with concurrent AD and IBD (a rare but clinically challenging scenario) the use of biologics targeting type 2 inflammation should be undertaken with great caution, and a detailed individualized risk-benefit assessment is essential.

Small Molecule Inhibitors

JAK Inhibitors

In the neuroimmune pathway activated by IL-4/IL-13, the JAK-STAT pathway play an important role.²⁰⁰ Oral JAK inhibitors, such as upadacitinib and abrocitinib, have emerged as important complements to biologics, offering significant advantages in rapid onset of action and convenience of administration. To date, upadacitinib has received FDA approval in both major disease areas, AD and inflammatory bowel disease (IBD);^203,204 abrocitinib has been approved for AD,²⁰⁵ collectively demonstrating the broad application prospects of this class of agents. However, the FDA boxed warning for JAK inhibitors, including risks of serious cardiovascular events, thrombosis, and malignancy, significantly limits their use beyond low‑risk patients.²⁵¹ Moreover, whether differences in subtype selectivity among JAK inhibitors translate into differential clinical benefits remains unresolved, as direct randomized clinical trials are currently lacking.²⁵²

MyD88 Inhibitors

Myeloid differentiation factor 88 (MyD88) is a key adaptor protein downstream of the TLR/IL‑1R pathway, which activates NF‑κB and MAPK signaling and sensitizes sensory neurons through IL‑1β/TNF‑α.^206,207 INNA1605 (topical formulation) is a first‑in‑class small‑molecule MyD88 inhibitor that has completed Phase I clinical trials (registration number: CTR20244849) and is currently undergoing Phase II trials for psoriasis and AD.

Neuromodulatory Drugs

Cannabinoids

Cannabinoids are a sort of lipophilic compounds. They are structurally related to Δ 9-tetrahydrocannabinol (THC), which is the main psychoactive ingredient in cannabis, or bind to the same classical pharmacological receptor sites.²⁵³ Both endogenous and exogenous cannabinoids can activate the cannabinoid receptors CB1 and CB2.²⁵⁴ These two receptors are similar in structure, what differs is that their genes are located on different chromosomes (human chromosome 6 and chromosome 1, respectively), and they have different tissue distributions and physiological characteristics.^255,256 More specifically, CB1 receptors are highly expressed in the CNS. Their activation may severely impact the ability of neuronal tissue to infect viruses.²⁵³ The CB2 receptor is highly expressed on immune cells (such as mast cells and macrophages) and influences the progression of inflammation by modulating immune responses.²⁵⁷ In AD and psoriasis models, cannabinoid agonists have been shown to reduce neuropeptide release, alleviate pruritus, and improve barrier function;²⁰⁸ in IBD models, CB2 activation attenuates colitis severity.²⁰⁹ Current research efforts are directed toward peripherally restricted CB2 agonists or topical formulations (eg, β-caryophyllene) to circumvent central side effects.²¹⁰

TRPV1 Antagonists

TRPV1 on sensory neurons mediates pruritus, pain, and neuropeptide release.²⁵⁸ Asivatrev (PAC-14028), a non-competitive TRPV1 antagonist, not only significantly suppresses pruritic behavior in AD models but also reduces skin barrier damage and inflammatory cell infiltration, demonstrating favorable efficacy in Phase III clinical trials.^211,212 In colitis models, TRPV1 blockade likewise alleviates visceral hypersensitivity and intestinal inflammation, suggesting that this target holds dual therapeutic value for both the skin and the gut.²¹³ Of note, several earlier TRPV1 antagonists (eg, AMG 517) failed due to mechanism-related hyperthermia and impaired heat sensation, effects arising from the physiological role of TRPV1 in thermoregulation.²⁵⁹ However, current clinical data indicate that Asivatrep is well tolerated, with no significant fever-related adverse events reported.²¹²

Cholinergic Anti-Inflammatory Drugs

The CAIP is a classic neuroimmune pathway, currently believed to be composed of the VN, ACh, and its receptors.²⁶⁰ This pathway can activate and regulate the activity of immune cells, inhibit cell proliferation and differentiation, and suppress cytokine release, thereby exerting anti-inflammatory effects and widely participating in the occurrence and development of various diseases.²⁶¹ Cholinergic anti-inflammatory drugs activate their anti-inflammatory effects by targeting the central or peripheral parts of CAIP and mainly include the following subclasses:

α7nAChR Agonist

CAIP connects the nervous and immune systems. The α7-nicotinic acetylcholine receptor (α7nAChR) is a key protein in CAIP. The α7nAChR activator binds to the α7nAChR receptor, thereby activating CAIP, then inhibiting inflammatory mediators and regulating the immune cells’ function.²⁶² Currently, some α7nAChR activators (eg, PNU-282987 and GTS-21) have been demonstrated in preclinical studies to suppress the release of pro-inflammatory cytokines.^214,215 In animal models of ulcerative colitis, α7nAChR agonists alleviate intestinal mucosal inflammation and improve barrier function;²¹⁶ in skin inflammatory models such as psoriasis, activation of this pathway has also shown potential in suppressing inflammatory cell infiltration and relieving pruritus.²¹⁴

Central Action AChE Inhibitors

Recent evidence suggests that cholinergic neurons in the medial septal/diagonal band area can project to downstream region, where cholinergic transmission occurs, by activating postsynaptic M1 muscarinic receptors.²⁶³ This pathway can activate the central muscarinic receptor-mediated VN and α7nAChR dependent mechanism by inhibiting brain AChE (eg, galantamine,²¹⁷ rivastigmine),²¹⁸ thereby inhibiting systemic TNF release and exerting systemic inflammation.²¹⁷ Agents such as galantamine and rivastigmine have shown promise in experimental models of inflammatory diseases including IBD,^219,220 and their potential value in cutaneous inflammation also warrants further exploration. However, the cholinergic system in the skin is complex in its actions, and the effects of AChE inhibition are not uniformly anti-inflammatory. Moreover, their ability to penetrate the blood-brain barrier and the associated central side effects (particularly with respect to cognitive function) constitute major obstacles to their clinical translation.²⁶⁴

mAChR Agonist

MAChRs are the main receptors for ACh binding and signaling. They play an important role in regulating the PNS and CNS. M1 muscarinic receptor agonists (eg, McN-A-343) have shown promising preclinical evidence in the treatment of inflammatory bowel diseases such as ulcerative colitis, with diverse mechanisms of action.^221,222 In contrast, research on mAChR agonists in the field of inflammatory skin diseases remains at a very early stage, primarily focusing on explorations of receptor function.²²³

AR Agonists

Research on adrenergic receptor (AR) agonists in this field presents a notable characteristic: the effects of different subtypes (α vs β) are diametrically opposed, and even within the same subtype, different agonists may produce completely opposite outcomes.

In intestinal inflammation studies, β3-AR agonists have demonstrated positive therapeutic potential. For instance, mirabegron (an approved drug for overactive bladder) significantly alleviates colonic injury and inflammation in various animal models of colitis, primarily through activation of the antioxidant Nrf2-HO-1 signaling pathway. To enhance efficacy and reduce systemic side effects, recent research has employed prodrug design for colon-targeted delivery, with one derivative (MAS-Glu) showing even greater therapeutic efficacy than the clinically used sulfasalazine.²²⁴ In contrast, activation of α2-AR exacerbates disease. Studies have clearly shown that the non-selective α2-AR agonist clonidine worsens colitis in mice, and this detrimental effect is primarily mediated by the α2A-AR subtype.²⁶⁵ Consequently, the use of α2-AR antagonists is instead considered a promising therapeutic strategy.

In the field of skin inflammation, exploration of AR agonists is more diversified. β2-AR agonists have been more extensively studied. The long-acting β2-AR agonist salmeterol has been shown to ameliorate psoriasiform skin lesions by activating the cAMP/PKA signaling pathway, which inhibits excessive keratinocyte proliferation and promotes apoptosis.²²⁵ Research on α2-AR agonists has mainly focused on brimonidine, which is currently approved for the treatment of facial erythema in rosacea, primarily through its vasoconstrictive effect on cutaneous blood vessels.²²⁶

Non-Pharmacologic Interventions

Based on neuroimmune regulatory mechanisms, physical intervention modalities have gained extensive attention in recent years due to their non-invasive or minimally invasive nature. Currently, these mainly include vagus nerve stimulation (VNS), peripheral focused ultrasound stimulation (pFUS), and acupuncture, which exert anti-inflammatory effects by directly or indirectly activating neuroimmune pathways.

VNS

In various inflammatory diseases including IBD, VNS transmits signals via its afferent fibers to efferent fibers, thereby activating the CAIP and eliciting anti-inflammatory or immunomodulatory effects.^266,267 Based on this, clinical trials using VNS to treat related diseases continue to emerge. VNS can be divided into invasive VNS (iVNS) and transcutaneous VNS (tVNS).

iVNS requires surgical implantation of electrodes and has been used for refractory epilepsy and depression, but carries risks of surgery and adverse effects.²²⁷ tVNS, which non-invasively delivers electrical current via the auricular or cervical skin, offers a significantly improved safety profile and has shown promise in interventions for gastrointestinal inflammatory disorders such as IBD.^228,229 Although several reviews have reported that direct VNS can effectively alleviate IBD symptoms without serious adverse events, the lack of large-scale, high-quality randomized controlled trials remains a major barrier to the clinical translation of VNS in IBD.^230,231

PFUS

PFUS is an emerging non-invasive neural stimulation technique that simultaneously possesses the ability to stimulate and inhibit neuronal activity,¹³ making it a powerful tool for targeting multiple types of nerves. At present, relevant experiments have shown that the application of pFUS to the spleen can inhibit inflammation caused by LSP. The mechanism is that it activates the spleen CAIP by stimulating the sympathetic nervous system in the tissue to release NE, thereby regulating immune effects.^268,269 However, the therapeutic application of this technology in inflammatory skin and intestinal diseases remains largely at the preclinical stage, with no formal human clinical trials conducted to date.

In the IBD field, pFUS has accumulated a certain body of evidence from animal models. For example, in a DSS-induced rat colitis model, non-invasive focused ultrasound targeting the celiac plexus significantly improved stool consistency and bleeding scores, restored colon length, and brought inflammatory cytokine levels (IL-1 β, IL-6, TNF-α) close to normal.²³² Another study demonstrated that therapeutic ultrasound (TUS) exerts anti-colitis effects by stimulating the splenic nerve and activating the CAIP, and that splenectomy or α7nAChR knockout completely abolished this protective effect.²³³ Recent research has further revealed that low-intensity pulsed ultrasound (LIPUS) to the spleen induces molecular alterations in neuroimmune-related pathways in the prefrontal cortex (involving Notch signaling), providing new mechanistic insights into the “spleen–brain axis” regulation and non-invasive intervention for IBD.²³⁴

In the field of inflammatory skin diseases, evidence for the therapeutic application of pFUS is even more scarce. In existing studies, high-intensity focused ultrasound (HIFU) has been used primarily as a diagnostic tool for assessing pain sensitivity in inflamed tissues rather than as a therapeutic modality.²⁷⁰ Beyond the paucity of clinical evidence, the clinical translation of pFUS also faces two major technical challenges: standardization of stimulation parameters and targeting precision.²³⁵

Acupuncture and Moxibustion Therapy

Acupuncture and moxibustion stimulation primarily encompass two modalities: manual acupuncture (MA) and electroacupuncture (EA). The core anti-inflammatory mechanism lies in regulating somato-autonomic reflexes through stimulation of specific acupoints, thereby reshaping neuroimmune homeostasis.²³⁶

Acupuncture has accumulated a considerable body of clinical research in IBD, particularly in UC; however, more high-quality evidence is still needed to confirm its efficacy. Several meta-analyses have suggested positive therapeutic effects of acupuncture in IBD. For instance, one meta-analysis showed that acupuncture effectively modulated levels of inflammatory cytokines such as TNF-α, IL-8, and IL-10 in IBD patients.²³⁷ Another network meta-analysis, which included 76 randomized controlled trials (RCTs) involving 7,484 patients with UC, demonstrated the substantial volume of clinical research in this area.²³⁸ Nevertheless, the autonomic regulatory effects of acupuncture are influenced by multiple factors, including acupoint specificity, stimulation intensity, frequency, and disease status; the lack of standardized treatment protocols limits its broad clinical application.

In inflammatory skin diseases, however, most clinical studies are small-sample trials. For example, a 2025 RCT explored the efficacy of auricular acupuncture as an adjunctive therapy for AD;²³⁹ another 2023 study investigated the feasibility of degradable microneedle acupuncture for mild-to-moderate AD.²⁴⁰ Nonetheless, authoritative guidelines (eg, the 2020 recommendations of the Polish Dermatological Society) explicitly advise against the use of acupuncture for AD.²⁴¹ Research in this area remains at an exploratory stage.

Conclusion and Prospect

Neuroimmune interactions constitute a complex and finely orchestrated process, involving an array of neuropeptides, cytokines, and their cognate receptors, with the anatomical co-localization of immune cells and neurons further facilitating such cross-talk. As major barrier organs of the body, the skin and the gut share analogous structural and immunological features, and their sensory functions as well as pro-or anti-inflammatory responses are critically dependent on reciprocal neuroimmune regulation. In both tissues, neuropeptides (eg, SP, CGRP, and VIP) released from nerve fibers act on respective receptors on mast cells, dendritic cells, macrophages, and T cells, thereby modulating degranulation, activation, migration, infiltration, and the secretion of inflammatory cytokines, consequently influencing the inflammatory cascade. Conversely, inflammatory and pruritogenic mediators liberated by immune cells can reciprocally regulate neuropeptide release from nerve fibers, contributing to the genesis of itch and pain, thus forming an intricate bidirectional regulatory network between the nervous and immune systems. Notably, the underlying neuroimmune mechanisms exhibit distinct features across different neurogenic inflammatory conditions. For instance, AD and psoriasis are predominantly driven by Th2-type and Th1/Th17-type immune responses, respectively, with neuropeptides also affecting keratinocyte proliferation and thereby sustaining cutaneous inflammation. The intestinal tract, however, possesses unique characteristics attributable to the gut-brain axis and its intrinsic ENS, where neuroimmune interactions may also exert protective effects against bacterial-driven inflammation.

Building upon the reciprocal interplay between cutaneous and intestinal inflammation, several agents targeting specific immune pathways have received marketing approval. For shared pivotal pathways, biologics directed against key cytokines (eg, TNF-α, IL-12/23) and neuromodulatory compounds such as cannabinoids are currently in use. It is noteworthy that, while certain cytokine-targeting agents have been validated in vitro and in animal models and have accrued some clinical experience, a substantial proportion of candidates remain in clinical trials or even preclinical stages, with their efficacy yet to be fully established. Non-pharmacological interventions, meanwhile, continue to face challenges including a paucity of large-scale randomized controlled evidence and issues related to targeting precision.

Future investigations should place greater emphasis on the pathophysiological specificity of distinct neurogenic inflammatory diseases, so as to refine the precision of neuroimmune-circuit-directed interventions. The clinical validation of novel therapeutics will require larger, well-characterized patient cohorts and validation at the human tissue level, in order to generate high-quality clinical evidence and enhance therapeutic safety. Given the holistic and complex nature of neuroimmune networks, approaching the skin and gut as an integrated organic entity may represent a promising perspective for future research and therapeutic strategies.

Funding Statement

This research was supported by Natural National Science Foundation of China (No. 82573291).

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Meiling Huang: Conceptualization, Investigation, Writing-original draft, Writing-review & editing; Meng Yang: Formal analysis, Writing-original draft, Writing-review & editing; Tianhong Shen: Formal analysis, Writing-original draft, Writing-review & editing; Aoyang Long: Visualization, Formal analysis, Writing-original draft, Writing-review & editing; Mingyang Gao: Visualization, Formal analysis, Writing-original draft, Writing-review & editing; Yuzhe Wang: Visualization, Formal analysis, Writing-original draft, Writing-review & editing; Wenhao Shan: Formal analysis, Writing-original draft, Writing-review & editing; Zijian Ye: Formal analysis, Writing-original draft, Writing-review & editing; Qiang Wu: Formal analysis, Writing-original draft, Writing-review & editing; Gangcai Zhu: Funding acquisition, Formal analysis, Writing-original draft, Writing -review & editing; Xueyang Li: Formal analysis, Writing-original draft, Writing-review & editing; Manlin Hu: Visualization, Conceptualization, Writing-original draft, Writing-review & editing; Yuyang Xiao: Conceptualization, Project administration, Supervision, Investigation, Writing-original draft, Writing-review & editing. All authors gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

Dr Wenhao Shan reports Support for this work from medical writing, during the conduct of the study. All other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this review.