Beyond Histamine: Mast Cell‐Neuron Communication in Chronic Pruritic and Pain Disorders

ABSTRACT

Chronic pruritic and cutaneous pain disorders are increasingly recognized as neuroimmune conditions driven by dynamic interactions between immune and sensory systems. While histamine has historically dominated models of mast cell‐mediated itch, accumulating evidence indicates that non‐histaminergic pathways are central to chronic disease. In this review, we synthesize current understanding of mast cell‐neuron communication and propose a unifying framework in which these cells form functional neuroimmune units that sustain itch and pain through bidirectional signalling and feed‐forward amplification. Mast cells release proteases, cytokines, lipid mediators, and neurotrophins that activate and sensitize sensory neurons via receptors including PAR‐2, IL‐31RA, TrkA, and transient receptor potential channels. In parallel, neuron‐derived neuropeptides such as substance P and calcitonin gene‐related peptide drive mast cell activation, notably through MRGPRX2‐dependent mechanisms, reinforcing neurogenic inflammation. These interactions promote peripheral sensitization and structural remodelling of cutaneous innervation, providing a mechanistic basis for persistent symptoms across disorders such as atopic dermatitis, prurigo nodularis, urticaria, neuropathic itch, and chronic pruritus of unknown origin. Importantly, emerging therapies targeting key nodes of this axis ‐ including IL‐4Rα, IL‐31RA, KIT, and Bruton's tyrosine kinase—offer clinical validation of this neuroimmune paradigm. We highlight critical gaps in translating these insights to human disease, including the need for spatially resolved biomarkers and real‐time functional mapping of neuroimmune interactions. Advancing this framework may enable precision‐targeted therapies for chronic itch and skin pain conditions that remain refractory to conventional treatment.

1. Introduction

Chronic pruritus and pain are debilitating sensory disorders traditionally viewed through a histamine‐centric framework, in which mast cells trigger symptoms via histamine release and activation of sensory neurons [1]. This model, exemplified by urticaria, positioned antihistamines as first‐line therapy. However, more chronic pruritic and pain disorders respond poorly to antihistamines, indicating that histamine plays a limited role in persistent disease [2, 3].

Advances in neuroimmune biology have redefined mast cell‐neuron communication as a complex, bidirectional axis involving proteases, lipid mediators, cytokines (IL‐4, IL‐13, IL‐31, TNF), neutrophils, and neuropeptides acting through receptors such as PAR‐2, IL‐31RA, TrkA, and MRGPRX2 [4, 5, 6, 7, 8]. These interactions drive non‐histaminergic itch and pain pathways and sustain neurogenic inflammation through feed‐forward loops and structural remodelling of peripheral nerves [1, 6].

Critically, this communication is bidirectional: sensory neurons release neuropeptides such as Substance P (SP), calcitonin gene‐related peptide (CGRP), and vasoactive intestinal peptide (VIP) that activate mast cells through receptors like MRGPRX2, generating feed‐forward neurogenic inflammation and structural remodelling that sustains peripheral sensitization [1, 4, 6, 7, 9].

Chronic itch is encoded primarily through non‐histaminergic neuronal circuits involving keratinocyte‐immune‐neural crosstalk [10]. Targeted therapies demonstrate superior efficacy over antihistamines in atopic dermatitis and prurigo nodularis. However, significant gaps remain in our mechanistic understanding of how specific mast cell mediators activate distinct neuronal populations, how these interactions vary across different tissue microenvironments, and how to optimally target these pathways therapeutically.

This review summarizes non‐histaminergic mast cell‐neuron communication, its molecular mechanisms, disease relevance, and therapeutic implications in chronic pruritic and cutaneous pain disorders. By moving beyond the historical histamine paradigm, we aim to provide a comprehensive framework for understanding and treating chronic itch and skin pain through the lens of neuroimmune biology.

2. Mast Cell Biology and Anatomical Proximity to Neurons

Mast cells are tissue‐resident immune cells derived from haematopoietic progenitors that complete differentiation within peripheral tissue under the influence of stem cell factor (KIT ligand) [11, 12, 13]. Their developmental plasticity results in organ‐specific phenotypes, with distinct transcriptomic subsets identified across tissues, including skin‐enriched populations [12].

Mast cells are abundant at host‐environment interfaces such as skin, lung, and gut, where they localize near blood vessels and peripheral nerve fibres [14, 15].

Mast cells and sensory neurons form closely apposed neuroimmune units, often separated by nanometre distances in skin and other tissues [4, 16, 17]. Increased mast cell‐nerve contacts and synapse‐like structures are observed in chronic inflammatory conditions such as atopic dermatitis and psoriasis [1]. This proximity enables rapid mediator exchange: mast cells release pruritogens and algogens that activate neuronal receptors, while neurons release neuropeptides such as substance P that induce MRGPRX2/Mrgprb2‐mediated mast cell degranulation [16, 18]. This bidirectional communication is facilitated by the expression of complementary receptor‐ligand pairs: mast cells express receptors for neuropeptides and neurotransmitters, while sensory neurons express receptors for mast cell‐derived mediators including histamine, tryptase, cytokines, and neurotrophins [1, 19]. Recent evidence suggests that certain neuronal subtypes, such as MRGPRD‐expressing nonpeptidergic neurons, can also suppress mast cell activation via glutamate release, revealing additional layers of complexity in neuroimmune regulation [20].

3. Modes of Mast Cell Activation in Skin

Mast cell activation in the skin occurs through two principal mechanisms that differ in triggers, signalling pathways, and clinical relevance: IgE/FcεRI‐mediated activation and non‐IgE‐mediated activation, particularly via MRGPRX2.

The classical pathway of mast cell activation involves cross‐linking of immunoglobulin E (IgE) bound to the high‐affinity Fc epsilon receptor I (FcεRI) on the mast cell surface. This mechanism underlies immediate hypersensitivity reactions and is relevant to diseases such as chronic spontaneous urticaria (CSU) and inducible urticarias [21, 22]. Activation leads to rapid degranulation and release of histamine, tryptase, and other preformed mediators, resulting in vasodilation, increased vascular permeability, and acute itch. Although histamine is a dominant mediator in this pathway, accumulating evidence indicates that cytokines, lipid mediators, and neuropeptides also contribute to symptom generation and chronicity [10, 21].

In contrast, non‐IgE‐mediated activation, particularly via MRGPRX2, enables mast cells to respond directly to cationic peptides, neuropeptides, and pharmacologic agents in the absence of prior sensitization. Substance P is a key endogenous agonist in this context, linking sensory neuron activation to mast cell degranulation. MRGPRX2‐dependent signalling has been increasingly implicated in neurogenic inflammation and in chronic pruritic disorders that are refractory to antihistamines [7, 10, 16].

These pathways are not mutually exclusive and frequently coexist within the same disease context. However, their relative contribution differs across conditions and may shift over time, with IgE‐dependent mechanisms more closely associated with acute responses and MRGPRX2‐driven signalling contributing to sustained neuroimmune activation [10, 23].

3.1. Histaminergic Signalling: Limitations in Chronic Conditions

Histamine, released during IgE‐mediated mast cell degranulation, activates H1 and H4 receptors on sensory C‐ and Aδ‐fibres, leading to transient receptor potential vanilloid 1 (TRPV1)‐dependent and Nav‐dependent neuronal depolarization and acute itch or pain [24, 25, 26]. This pathway is exemplified by urticaria, where antihistamines are effective [27].

In contrast, chronic pruritic disorders such as atopic dermatitis are driven predominantly by non‐histaminergic pathways involving Th2 cytokines (particularly IL‐4, IL‐13, and IL‐31), proteases, and neuropeptides [23]. Guidelines therefore restrict antihistamine use to histamine‐mediated conditions such as urticaria [28].

Histaminergic itch is transmitted via TRPV1‐expressing neurons, whereas non‐histaminergic itch involves TRPA1‐dependent pathways activated by pruritogens such as chloroquine, cowhage (mucunain), and PAR‐2 agonists [29]. In atopic dermatitis, patients exhibit selective sensitization to non‐histaminergic stimuli, while histamine responses remain comparable to controls, confirming pathway‐specific amplification of non‐histaminergic circuits [30]. This non‐histaminergic sensitization contributes to the ‘itch‐scratch‐itch cycle’ that perpetuates chronic pruritus and worsens skin lesions [30].

4. Non‐IgE‐Mediated Mast Cell‐Neuron Signalling in Skin

Non‐IgE mediated and non‐histaminergic signalling have emerged as central mechanisms underlying chronic pruritus and cutaneous pain, particularly in conditions that respond incompletely to antihistamines. In the skin, these pathways are mediated by dynamic, bidirectional communication between mast cells and sensory neurons, involving proteases, lipid mediators, cytokines, neurotrophins, and neuropeptides that converge on shared neuronal signalling pathways, including TRP channels [10, 23]. This non‐histaminergic mast cell‐neuron communication can be organized into mast cell‐derived signals acting on neurons, neuron‐derived signals acting on mast cells, and cytokines arising from the broader inflammatory milieu (Figure 1).

FIGURE 1.

The mast cell‐neuron neuroimmune unit in chronic itch and pain. Schematic illustrating the bidirectional communication loop driving chronic itch and pain. Mast cell activation is governed by IgE‐mediated pathways (via FcεRI and BTK signalling) and non‐IgE‐mediated pathways (primarily MRGPRX2), with c‐KIT signalling serving as a critical regulator of mast cell homeostasis and sensitivity. Extensive degranulation releases preformed mediators like tryptase, alongside cytokines (IL‐4, IL‐13, IL‐31, TNF) and lipid mediators, which activate corresponding neuronal receptors such as PAR‐2, IL‐31RA, and IL‐4Rα to propagate neurogenic inflammation. This bidirectional conversation is completed by the neuronal release of neurotransmitters and neuromodulators (Substance P, CGRP, VIP) that bind to mast cell receptors, increasing intracellular calcium and reinforcing a self‐amplifying sensitization state. Downstream of the sensory neuron, peripheral sensitization diverges into distinct clinical phenotypes: Itch via TRPA1, pain via TRPV1 and Nav, and a mixed phenotype characterized by central sensitization.

These directional signalling pathways map onto the broader modes of mast cell activation, with IgE/FcεRI signalling predominantly associated with classical degranulation responses, and MRGPRX2‐driven activation closely linked to neuron‐derived stimuli and neurogenic inflammation. Human skin biopsy studies in prurigo nodularis further illustrate the convergence of these neuroimmune pathways: lesional skin shows markedly increased mast cell numbers compared to nonlesional skin, with the co‐localization of lymphocytes, mast cells, and proliferating nerve fibres perpetuating the itch‐inflammation cycle [31].

4.1. Mast Cell‐To‐Neuron Communication

Mast cells modulate sensory neuron activity through the release of proteases, lipid mediators, cytokines, and neurotrophins that directly engage neuronal receptors and ion channels.

4.1.1. Tryptase and Protease‐Activated Receptor‐2 (PAR‐2)

Among the most well‐characterized non‐histaminergic pathways, tryptase is the predominant mast cell protease, activating sensory neurons via PAR‐2 and contributing to itch and pain hypersensitivity [1, 6, 32]. PAR‐2 signalling enhances TRPA1 responsiveness and promotes peripheral sensitization [33]. The mast cell/tryptase/PAR‐2 axis has been implicated in inflammatory and musculoskeletal pain models [34].

In human skin, tryptase levels were increased up to fourfold in atopic dermatitis (AD) patients, with AD skin biopsies showing PAR‐2 markedly enhanced on primary afferent nerve fibres [35]. Intracutaneous injection of PAR‐2 agonists provoked enhanced and prolonged itch that persisted despite antihistamine treatment, identifying PAR‐2 as a non‐histaminergic link between mast cell activation and sensory phenomena in AD [35]. Furthermore, mast cell tryptase acting through PAR‐2 on keratinocytes instructs the production of thymic stromal lymphopoietin (TSLP), a key driver of type 2 inflammation, establishing an additional mast cell‐epithelial‐immune signalling axis relevant to AD pathogenesis [36].

4.1.2. Prostaglandins and Leukotrienes

In addition to protein mediators, mast cells synthesize and release lipid mediators including prostaglandins (particularly PGD₂ and PGE₂) and cysteinyl leukotrienes (LTC₄, LTD₄, LTE₄) that contribute to neurogenic inflammation and sensory neuron activation [5]. These mediators activate or sensitize pruriceptors and nociceptors, particularly the natriuretic polypeptide b (Nppb)‐expressing neurons that transmit itch via gastrin‐releasing peptide (GRP)‐dependent spinal pathway [37]. Prostaglandins sensitize nociceptors and pruriceptors by lowering their activation thresholds, enhancing responses to other pruritogenic and algogenic stimuli.

4.1.3. Tumour Necrosis Factor (TNF)

TNF released by mast cells serves as a critical sensitizer of nociceptive and pruriceptive nerve endings, enhancing their responsiveness to subsequent stimuli [5, 32]. TNF sensitizes sensory neurons through multiple mechanisms, including modulation of ion channel expression and function, enhancement of neurotransmitter release, and promotion of neuronal hyperexcitability.

In human skin, low concentrations of substance P can activate NK1 receptors on mast cells, leading to sensitization and increased production of TNF, which in turn sensitizes nociceptive nerve endings—providing direct evidence of extensive crosstalk between nerves and mast cells in human tissue [32].

4.1.4. Nerve Growth Factor (NGF)

NGF represents a key neurotrophic mediator in mast cell‐neuron communication that drives both acute sensitization and chronic structural changes in sensory innervation [1, 6]. Mast cells produce and release NGF, which binds to the high‐affinity tropomyosin receptor kinase A (TrkA) expressed on sensory neurons [1]. NGF exerts modulatory effects on sensory nociceptive nerve physiology, correlating with hyperalgesic and pruritic phenomena in tissue inflammation [5, 38]. NGF promotes neuronal survival, neurite outgrowth, and phenotypic changes in sensory neurons, while also enhancing neuronal sensitivity to pruritogenic and algogenic stimuli [39, 40]. Importantly, NGF creates bidirectional communication, as mast cells themselves express NGF receptors and respond to NGF with enhanced mediator production, suggesting that alterations in mast cell behaviour could provoke maladaptive neuroimmune responses [38, 39]. NGF concentrations are elevated in numerous inflammatory and autoimmune states, including chronic pruritic conditions, in conjunction with increased mast cell accumulation [38].

In human prurigo nodularis, dermal levels of NGF are increased alongside elevated substance P and CGRP, and this neurotrophin milieu is accompanied by a predominant presence of eosinophils and mast cells, supporting the role of NGF in driving the neural hyperplasia and mast cell‐nerve interactions characteristic of this condition [41, 42]. Chronic psychological stress further amplifies this axis in human skin, with increased dermal nerve fibre density, mast cell numbers, and NGF levels observed in chronic inflammatory skin diseases including prurigo nodularis and atopic dermatitis [43].

4.1.5. Serotonin (5‐Hydroxytryptamine)

Serotonin released by mast cells acts as a potent inflammatory mediator that modulates pain and itch sensing through activation of multiple serotonergic receptor subtypes on primary afferent neurons [5, 44]. Sensory neurons express 5‐HT₁A and 5‐HT₃ receptors that mediate sustained and transient effects, respectively, of serotonin on neurons involved in pain and itch processing [44]. Serotonin receptors are expressed by Nppb neurons, which serve as sensors of mast cell‐induced itch, with targeted receptor studies demonstrating the functional importance of serotonergic signalling in itch transmission [37, 45]. Among important mediators released by mast cells that induce pruritus, serotonin is distinguished alongside histamine, proteases, and cytokines as a key pruritogenic molecule [45].

4.2. Neuron‐To‐Mast Cell Communication

While mast cells play a central role in initiating non‐histaminergic signalling, sensory neurons are not passive targets but active participants in shaping mast cell responses. Sensory neurons actively regulate mast cell function through the release of neuropeptides, establishing a bidirectional signalling axis.

4.2.1. Substance P and MRGPRX2/Mrgprb2

Conversely, among the most well‐characterized neuron‐derived signals, substance P is a neuropeptide from the tachykinin family. Substance P represents the most extensively characterized neuronal mediator of mast cell activation and serves as a critical driver of neurogenic inflammation [16, 46]. Substance P is released from peptidergic C‐fibres and Aδ‐fibres in response to noxious stimuli, tissue injury, and inflammatory mediators, including those released by mast cells themselves [1, 46]. The discovery that Substance P activates mast cells primarily through the Mas‐related G protein‐coupled receptor X2 (MRGPRX2 in humans; Mrgprb2 in mice) rather than its canonical neurokinin‐1 receptor (NK‐1R) has fundamentally reshaped our understanding of neurogenic inflammation [7, 16]. MRGPRX2/Mrgprb2 is expressed specifically on connective tissue‐type mast cells and mediates non‐IgE‐dependent degranulation in response to cationic peptides and drugs [7, 16].

Substance P binding to MRGPRX2 induces rapid mast cell degranulation and cytokine release, establishing a feed‐forward loop in which mast cell‐derived proteases further activate sensory neurons and promote additional Substance P release [16, 47, 48]. This cycle sustains neurogenic inflammation and contributes to chronic pain and pruritus [48].

The functional significance of MRGPRX2/Mrgprb2 in neurogenic inflammation has been demonstrated across multiple disease models. Genetic deletion of Mrgprb2 abolishes Substance P‐induced inflammatory mechanical and thermal hyperalgesia and prevents recruitment of innate immune cells at injury sites [16]. Substance P‐induced lung inflammation in mice is entirely mast cell‐dependent, with Substance P triggering Th2‐type cytokine release (IL‐4, IL‐5, IL‐13) and contributing to allergic airway inflammation [49]. Naturally occurring missense variants in MRGPRX2 (G165E, D184H, W243R, H259Y) display complete loss of function for Substance P‐induced degranulation, suggesting genetic variability in susceptibility to neurogenic inflammation [50].

Emerging human clinical data further substantiate the relevance of the Substance P‐MRGPRX2 axis. In chronic prurigo, skin lesions exhibit markedly higher numbers of MRGPRX2‐expressing cells compared to nonlesional skin, with mast cells being the predominant MRGPRX2 mRNA‐expressing cells in 70% of patients. MRGPRX2 expression correlated with disease severity and serum MRGPRX2 levels correlated with quality‐of‐life impairment [51]. In chronic spontaneous urticaria (CSU), serum MRGPRX2 and substance P levels are significantly elevated in severe disease and serve as independent risk factors for severity, though they do not predict antihistamine response [52]. In atopic dermatitis, MRGPRX2/Mrgprb2 expression correlates with disease severity and type 2 cytokine levels independently of IgE, and tryptase released through MRGPRX2 activation initiates type 2 inflammation [53]. Novel potent and selective small molecule MRGPRX2 antagonists have demonstrated efficacy in blocking substance P‐mediated degranulation of freshly isolated human skin mast cells and inhibiting agonist‐induced degranulation in ex vivo human skin, supporting the therapeutic potential of targeting this receptor in mast cell‐driven skin disorders [54, 55].

4.2.2. Calcitonin Gene‐Related Peptide (CGRP)

CGRP, a neuropeptide co‐released with Substance P from peptidergic sensory neurons, plays complex and context‐dependent roles in mast cell activation and neuroimmune communication [56, 57, 58]. CGRP is expressed primarily in TRPV1+ C‐fibres and Aδ‐fibres and serves as a potent vasodilator and modulator of neurogenic inflammation [56, 58]. Unlike Substance P, CGRP's effects on mast cells are more variable, with evidence for both activating and modulatory functions depending on mast cell phenotype, tissue context, and co‐stimulatory signals [59, 60].

In vitro studies demonstrate that CGRP can induce mast cell degranulation, though typically with reduced chemical messenger content per secretion event compared to other stimuli [59]. CGRP‐induced mast cell activation shares biophysical characteristics with calcium ionophore‐induced degranulation but results in overall decreased secreted mediator content [59]. In visceral pain models, CGRP promotes mast cell activation and alters gene expression linked to proliferation and stress responses [60]. These findings suggest context‐dependent enhancement of mast cell function in chronic pain states.

In human allergic skin, CGRP‐immunoreactive and CGRP mRNA‐positive inflammatory cells are significantly increased in late‐phase skin reactions, peaking at 6 h after allergen challenge in parallel with the development of edema. The majority of CGRP‐positive cells were neutrophils and CD3+ T cells rather than eosinophils [61]. In chronic inflammatory skin diseases, CGRP levels are elevated alongside increased dermal nerve fibre density and mast cell numbers, and CGRP elicits a type 2‐polarized T‐cell response that is a hallmark of chronic pruritic conditions such as atopic dermatitis and prurigo nodularis, contributing to both acute pruritus and sensitization of cutaneous sensory neurons [42, 43].

4.2.3. Vasoactive Intestinal Peptide (VIP)

VIP, a neuropeptide belonging to the VIP/secretin/glucagon family, functions as a pleiotropic immunomodulator with complex effects on mast cell activation and inflammatory responses [62, 63]. VIP is released from both neuronal and immune cells (particularly Th2 cells) and exerts immunological functions through interaction with specific receptors—VPAC1, VPAC2, and PAC1—expressed on various immune cells including mast cells [62, 63]. VIP mediates tissue‐specific immunological actions depending on the presence of specific VIP‐associated receptors, involved immune cells, and the local microenvironment [63].

VIP induces mast cell degranulation and robust chemokine production through VPAC2‐mediated signalling [64]. Unlike IgE‐mediated activation, VIP responses preferentially promote chemotactic recruitment rather than classical allergic degranulation.

4.2.4. Glutamate and Inhibitory Neurotransmission

Recent evidence reveals that not all neuronal mediators activate mast cells; some neuronal populations actively suppress mast cell function, adding another layer of complexity to neuroimmune regulation [4, 20]. MRGPRD‐expressing nonpeptidergic sensory neurons suppress mast cell activation via glutamate release, with genetic ablation of these neurons resulting in increased mast cell degranulation and enhanced inflammatory responses [20]. This inhibitory neuron‐mast cell circuit maintains skin homeostasis and prevents excessive mast cell activation under baseline conditions [20]. The discovery of inhibitory neuronal control of mast cells suggests that the balance between activating (Substance P, CGRP, VIP) and inhibitory (glutamate from specific neuronal subsets) signals determines the net level of mast cell activity in tissues.

4.2.5. Cholinergic and Parasympathetic Regulation

Cholinergic and non‐adrenergic, non‐cholinergic (NANC) neurons also modulate mast cell function across multiple tissues [19, 65, 66]. Acetylcholine and other parasympathetic mediators can regulate mast cell degranulation, cytokine production, and chemokine release, though the specific effects vary by tissue context and mast cell phenotype [65, 66]. In chronic inflammation, positive feedback circuits—particularly the Substance P‐MRGPRX2 axis—sustain neurogenic signalling and represent therapeutic targets including MRGPRX2 and neuropeptide receptor antagonists [1, 4, 67].

4.3. Inflammatory Cytokines and Signals

Among clinically relevant cytokine pathways, type 2 cytokines are released primarily by Th2 cells, as well as mast cells and other immune cells. These represent key drivers of chronic itch through direct neuronal effects and neuroimmune modulation [68, 69]. IL‐31, produced predominantly by Th2 cells and to a lesser extent by mast cells, acts as a potent pruritogen by binding to the heterodimeric IL‐31 receptor (IL‐31RA/OSMRβ) expressed on a subpopulation of TRPV1⁺/TRPA1⁺ dorsal root ganglia (DRG) neurons [68, 70]. The clinical significance of IL‐31 signalling is validated by the efficacy of IL‐31RA antagonists such as nemolizumab in reducing pruritus in atopic dermatitis and prurigo nodularis [70, 71].

IL‐4 and IL‐13, acting through the shared IL‐4 receptor α (IL‐4Rα) subunit, exert pleiotropic effects on sensory neurons that extend beyond direct pruritogenic actions [69]. These cytokines promote DRG sensory neuron growth with effects similar to or greater than IL‐31, increase epidermal nerve fibre density, and induce broad transcriptomic changes in sensory neurons [69]. The IL‐4/IL‐13‐IL‐4Rα axis regulates inflammatory skin nerve innervation, neuroimmune interactions, barrier integrity, and itch responses, with itch‐associated genes upregulated by IL‐4 and IL‐13 showing positive correlation with atopic dermatitis severity [69]. The therapeutic efficacy of dupilumab, an IL‐4Rα antagonist, in reducing pruritus validates the central role of this pathway in chronic itch [2].

Collectively, these findings support a model in which mast cells and sensory neurons engage in a self‐reinforcing feedback loop. Mast cell‐derived mediators enhance neuronal excitability, while neuron‐derived signals further activate mast cells, creating a cycle that may underlie the persistence and amplification of chronic itch and pain. Importantly, the strength of evidence supporting individual neuroimmune pathways varies considerably. Certain cytokine pathways, particularly IL‐4/IL‐13 signalling through IL‐4Rα and IL‐31 signalling through IL‐31RA, have been directly validated in human disease through the clinical efficacy of targeted therapies in atopic dermatitis and prurigo nodularis [2, 72]. In contrast, several other pathways discussed in this review, including MRGPRX2‐mediated signalling, CGRP, VIP, serotonin, and inhibitory glutamatergic neuron‐mast cell interactions, are supported primarily by experimental studies, translational observations, and correlative human data [8, 73]. While these pathways represent promising therapeutic targets, definitive clinical validation through successful pathway‐specific interventions remains limited. This distinction is important when interpreting the relative translational maturity of the neuroimmune mechanisms described above.

5. Role in Specific Chronic Pruritic and Skin Pain Disorders

The mast cell‐neuron axis has been implicated in the pathophysiology of diverse chronic pruritic and pain disorders, with accumulating evidence demonstrating disease‐specific patterns of neuroimmune dysregulation that drive symptom chronicity and treatment resistance [5, 19].

5.1. Chronic Urticaria and Inducible Urticarias

Chronic urticaria, including chronic spontaneous urticaria (CSU) and chronic inducible urticarias (CIndU), represents prototypical mast cell‐derived skin diseases in which mast cell activation is central to pathogenesis. In CSU, both IgE‐mediated and autoimmune mechanisms involving autoantibodies against FcεRI or IgE contribute to mast cell activation [21].

While histamine is a major mediator of wheal formation and itch, the pathogenesis extends significantly beyond histamine. Mast cells, epithelial cells, sensory nerves and other immune cells interact through Th2 cytokines (IL‐4, IL‐13, IL‐31), neuropeptides, and further mast cell activation through MRGPRX2, contributing to disease complexity, vasodilation, and increased vascular permeability [21, 22, 74]. The chronicity of urticaria leads to sustained pruritic symptoms contributing to both central and peripheral sensitization, with excitation of the itch circuit augmented by neurotransmitter and neuropeptide release that subsequently interacts with immune cells [74].

5.2. Urticaria Pigmentosa

Urticaria pigmentosa (maculopapular cutaneous mastocytosis) is characterized by abnormal accumulation of mast cells in the skin, with pruritus being a prominent symptom [13, 45]. Cutaneous mast cells in lesional skin contain elevated levels of histamine, tryptase, leukotrienes, prostaglandin D2, and platelet‐activating factor, and retain functional reactivity to secretory stimuli [75].

Pruritus in urticaria pigmentosa involves both histaminergic and non‐histaminergic pathways. Mast cells release pruritogenic mediators including histamine, serotonin, and proteases that activate receptors on sensory nerve fibres (H1, H4, PAR‐2, IL‐31R, TrkA) [1, 45]. Sensory nerves reciprocally release neuropeptides, substance P, neurokinin A, CGRP, and nerve growth factor that reactivate mast cells, perpetuating neurogenic inflammation [45]. The MRGPRX2/Mrgprb2 receptor mediates non‐histaminergic itch through mast cell activation independent of the IgE‐FcεRI‐histamine axis, which may explain antihistamine‐refractory pruritus in some patients [7, 76].

5.3. Atopic Dermatitis

In Atopic Dermatitis (AD), mast cells function within a broader skin neuroimmune ecosystem rather than acting as the sole driver of inflammation. Pruritus in AD is mediated by signalling between pruritogens released by keratinocytes, mast cells, and immune cells and small sensory nerve fibres in the skin [23]. Mast cells positioned in close proximity to sensory nerve endings release pruritogenic mediators including histamine, tryptase, and NGF, while also modulating IL‐31 signalling pathways [6]. These mediators act on neuronal receptors such as IL‐31RA, PAR‐1/2, TrkA, and P2X3, enhancing neuronal excitability and sensitizing TRP channels (TRPV1, TRPA1) [6]. Conversely, sensory neurons release substance P that activates MRGPRX2 on mast cells, inducing non‐IgE‐mediated degranulation and driving a feed‐forward itch‐inflammation loop [4, 6]. Structural adaptations including intraepidermal nerve fibre branching and synapse‐like mast cell‐neuron junctions provide anatomical substrates for chronic peripheral sensitization [1, 6].

5.4. Prurigo Nodularis

Prurigo nodularis (PN) is characterized by intense neuroimmune interactions, one of which is mast cell‐nerve bidirectional communication. Histopathological studies demonstrate marked increases in both mast cell density (assessed by toluidine blue staining) and neural hyperplasia (S‐100 expression) in lesional compared to nonlesional skin [31]. The pathogenesis is driven by a coordinated network of inflammatory cytokines (IL‐4, IL‐13, IL‐17, IL‐22, IL‐31) and neuropeptides (Substance P, CGRP) that perpetuate the itch‐scratch cycle [41]. Critically, cortistatin and its receptor MRGPRX2 are significantly upregulated in PN lesions, with mast cells being MRGPRX2‐expressing cells in most patients (70%) [51]. MRGPRX2 expression correlates with disease severity and quality‐of‐life impairment, supporting its role as both a biomarker and therapeutic target [51]. The promising effects of the KIT antibody barzolvolimab in early clinical trials have highlighted the crucial role of mast cells in PN pathophysiology [77]. Pruritus in PN is stimulated by the release of tryptase, IL‐31, prostaglandins, and neuropeptides from inflammatory cells, mast cells, and nerve fibres [78]. Phase III trials of nemolizumab have demonstrated significant reductions in itch and skin lesions, validating IL‐31 as a key mediator in this neuroimmune circuit [72].

5.5. Chronic Pruritus of Undetermined Origin

Mast cells likely contribute to itch in chronic pruritus of undetermined origin (CPUO) through non‐histamine‐dominant neuroimmune signalling [79, 80]. As mentioned above, beyond classical histamine release, mast cells secrete pruritogenic mediators such as tryptase, cytokines (e.g., IL‐4, IL‐13), and neuroactive factors that activate or sensitize cutaneous sensory nerves via receptors including PAR‐2 and MRGPRX2 [6, 7, 8]. In CPUO, where overt inflammation is minimal, low‐grade mast cell activation and close mast cell‐nerve interactions may lower neuronal activation thresholds and sustain peripheral sensitization [79, 80]. This mechanism helps explain the limited efficacy of antihistamines for CPUO and highlights mast cells as a therapeutic target, particularly via Bruton's tyrosine kinase (BTK) inhibitors. These inhibitors can suppress mast cell activation and degranulation, and through modulation of MRGPRX2‐mediated signalling pathways, represent promising non‐histaminergic strategies for refractory itch.

5.6. Cutaneous Neuropathic Itch and Pain

Mast cells contribute to neuropathic pain and itch in small fibre neuropathy (SFN) and postherpetic neuralgia (PHN) through temporally distinct mechanisms.

Acute degranulation following nerve injury releases preformed mediators including histamine and serotonin that recruit immune cells and initiate hyperalgesia [81, 82]. This early phase predominantly drives pain through direct nociceptor activation and inflammatory cell recruitment, with mast cell stabilizers reducing hyperalgesia development when administered early [82].

However, chronic sensitization involves sustained mast cell‐nerve feedback loops that preferentially promote itch. Mast cell tryptase activates PAR‐2 receptors on C‐fibre terminals, which release substance P that reactivates mast cells via NK1 receptors, creating a self‐perpetuating neurogenic inflammation loop [32]. Mast cells release algogenic and pruritogenic mediators that activate nociceptors, which release substance P that reactivates mast cells via MRGPRX2/Mrgprb2, perpetuating neurogenic inflammation [5, 16].

In SFN, mast cells are positioned near damaged peripheral nerve terminals where dysregulated activation contributes to both pain and itch [83, 84]. In diabetic SFN, high glucose triggers mast cell degranulation with release of histamine, tryptase, and inflammatory mediators that directly damage the neural microenvironment [85].

In PHN itch, intrinsic nerve damage from varicella‐zoster virus generates pathologic nerve impulses manifesting as both pain and itch [2, 86]. Specific mast cell mediators may preferentially activate itch versus pain pathways, mainly through histamine‐independent mechanisms [2, 5]. In complex regional pain syndrome (CRPS), altered mast cell proximity to dermal nerve fibres suggests disrupted neuroimmune interactions contributing to pain pathophysiology [84].

5.7. Rosacea

Mast cells are key mediators of the neuroimmune axis in rosacea. Increased dermal mast cells are activated by cathelicidin LL‐37 via MRGPRX2, triggering release of tryptase, chymase, and MMP‐9 that amplify inflammation and promote vasodilation [87, 88]. Sensory nerves are closely associated with mast cells in rosacea skin, and nerve‐derived neuropeptides activate mast cells, which release mediators that re‐sensitize TRPV1‐expressing neurons, thus establishing a bidirectional neurogenic inflammatory loop [89, 90]. MRGPRX2 antagonists reduce rosacea‐like inflammation in mouse models, supporting this receptor as a therapeutic target at the mast cell–neuron interface [87].

5.8. Hidradenitis Suppurativa

Mast cells are upregulated in Hidradenitis Suppurativa (HS) lesional tissue, with activated mast cells increased and resting mast cells decreased compared to non‐lesional skin [91]. Mast cell counts correlate with disease severity and itch intensity [92]. Itch occurs in 35%–83% of HS patients and often co‐localizes with pain; proposed mechanisms include peripheral sensitization, dense mast cell infiltration, and elevated IgE [93, 94]. HS‐associated itch is typically episodic rather than chronic, distinguishing it from atopic dermatitis, and may involve both nociceptive and neuropathic components [94, 95]. IL‐17A‐expressing mast cells are elevated in advanced HS and reduced by anti‐IL‐17 therapy [96].

6. Therapeutic Implications and Emerging Targets

The recognition that chronic pruritic and pain disorders are driven by non‐histaminergic mast cell‐neuron communication has catalysed the development of targeted therapies that address the mechanistic complexity of these conditions beyond traditional antihistamines [76, 97]. Current and emerging therapeutic strategies target multiple nodes of the neuroimmune axis, including mast cell depletion, cytokine blockade, receptor antagonism, and intracellular signalling inhibition (Figure 2). Some treatments directly interrupt mast cell function, while others block downstream mediators of neuronal sensitization.

FIGURE 2.

Therapeutic approaches in the mast cell‐neuron unit. Schematic detailing existing and experimental therapeutic approaches focused on the neuroimmune interface. Current and emerging treatments include inhibiting mast cell function and accumulation via anti‐KIT (e.g., barzolvolimab) and BTK inhibitors (e.g., remibrutinib, rilzabrutinib), as well as blocking specific receptor activation (e.g., MRGPRX2 antagonists). Primary drivers of feed‐forward loops are suppressed by cytokine signalling antagonists, including IL‐4Rα (e.g., dupilumab) and IL‐31RA (e.g., nemolizumab) inhibitors, alongside JAK inhibitors. Downstream, neuromodulators suppress neuronal sensitization to inhibit the processing of itch, pain, and mixed phenotypes at both the peripheral and central levels.

6.1. KIT Inhibition, Mast Cell Depletion and BTK Inhibitors

Traditional mast cell stabilizers such as cromolyn sodium and ketotifen have demonstrated modest efficacy in mast cell‐mediated disorders, though their clinical utility in chronic pruritus remains limited [13, 98]. A paradigm shift has emerged with the development of anti‐KIT monoclonal antibodies that deplete mast cells by inhibiting stem cell factor (SCF)‐mediated KIT activation [99, 100]. Barzolvolimab, an anti‐KIT antibody that depletes mast cells, has demonstrated significant clinical efficacy in chronic spontaneous and inducible urticaria, with responses paralleling mast cell depletion and tryptase suppression [97, 99].

Bruton's tyrosine kinase (BTK) inhibitors, including remibrutinib and rilzabrutinib, reduce mast cell activation through inhibition of FcεRI signalling, offering additional mast cell‐targeted approaches [101, 102]. Unlike KIT inhibitors, BTK inhibition preserves mast cells but prevents their IgE‐triggered degranulation, thereby interrupting the acute release of mediators that initiate the mast cell‐neuron feedback loop without affecting non‐IgE activation pathways such as MRGPRX2.

6.2. Receptor Antagonists and Ion Channel Modulators

Emerging therapies target receptors critical to mast cell‐neuron crosstalk, including MRGPRX2, PAR‐2, and TRP channels [6, 97]. MRGPRX2 antagonists represent a particularly promising class, as this receptor mediates non‐IgE‐dependent mast cell degranulation in response to substance P and other neuropeptides [54, 55]. Novel small molecule MRGPRX2 antagonists have demonstrated potent inhibition of agonist‐induced mast cell degranulation in vitro, in vivo, and ex vivo in human skin, supporting their therapeutic potential for mast cell‐mediated disorders including chronic urticaria and atopic dermatitis [55, 103]. TRP channel modulators targeting TRPV1 and TRPA1 offer additional therapeutic avenues by interrupting neuronal activation downstream of mast cell mediator release [6, 104].

6.3. Anti‐Cytokine Biologics

While these agents are best understood as interrupting the neuronal sensitization arm of the axis rather than the mast cell arm, anti‐cytokine biologics targeting the IL‐4/IL‐13 and IL‐31 pathways have revolutionized treatment of chronic pruritic conditions by interrupting cytokine‐mediated neuronal sensitization [2, 76].

Dupilumab, an IL‐4Rα antagonist blocking both IL‐4 and IL‐13 signalling, is FDA‐approved for atopic dermatitis, prurigo nodularis, and chronic spontaneous urticaria, with significant pruritus reduction observed in 55% of patients across clinical trials [2, 105]. Additional IL‐13‐targeting biologics including tralokinumab and lebrikizumab provide alternative options for patients with atopic dermatitis [105]. Nemolizumab, an IL‐31RA antagonist, directly targets the ‘itch cytokine’ pathway and is FDA‐approved for prurigo nodularis and moderate‐to‐severe atopic dermatitis, reducing pruritus in 56.3% of patients in phase 3 trials [2, 105].

6.4. JAK Inhibitors

JAK inhibitors have limited direct effects on mast cells. While ruxolitinib can inhibit substance P‐induced mast cell degranulation via JAK‐STAT5 blockade, this represents a secondary mechanism [106, 107]. The primary antipruritic effect of JAK inhibitors derives from broad suppression of cytokine receptor signalling (IL‐4, IL‐13, IL‐31) on multiple cell types including keratinocytes and sensory neurons [2]. JAK inhibitors should therefore be considered modulators of the inflammatory context surrounding the mast cell‐neuron axis rather than direct mast cell‐targeted therapies.

6.5. Major Open Questions and Future Directions

Despite significant advances in understanding mast cell‐neuron crosstalk, critical knowledge gaps remain that limit translation of mechanistic insights into precision therapies [5, 6]. Addressing these unmet needs will require innovative methodological research, robust biomarker development, and novel therapeutic strategies.

6.6. Spatiotemporal Signalling Dynamics

The real‐time understanding of bidirectional signalling remains opaque. Moving from static snapshots to functional mapping is essential. Genetically encoded biosensors show promise in dynamic precision dermatology research, allowing live imaging with high resolution on intracellular signalling [108, 109]. Applying these tools to neuroimmune clusters will clarify how their interactions translate into persistent itch and pain.

6.7. The Multicellular Ecosystem

A primary limitation is the focus on bi‐cellular models. We lack a clear understanding of how the mast cell‐neuron unit integrates signals from the broader inflammatory environment. Future studies must map the triad interaction between mast cells, sensory neurons, and neighbouring cells such as keratinocytes or other immune cells. This network‐level signalling likely dictates thresholds and pathways for chronic sensitization.

6.8. Novel Therapeutic Strategies

Future therapeutic development should focus on multi‐target interventions addressing the bidirectional nature of mast cell‐neuron communication [4, 6]. While current biologics target individual cytokines, combination approaches may provide superior efficacy. Emerging targets include MRGPRX2 antagonists currently in preclinical development, and understanding inhibitory neuron‐mast cell circuits, such as MRGPRD‐expressing neurons that suppress mast cell activation via glutamate, may reveal novel approaches for restoring neuroimmune homeostasis [4, 17].

7. Conclusions and Perspectives

The mast cell‐neuron axis has emerged as a central neuroimmune interface orchestrating bidirectional crosstalk between the immune and peripheral nervous systems in chronic pruritic and pain disorders [4, 6]. Moving beyond the traditional histamine‐centric paradigm, research has revealed a complex network of non‐histaminergic mediators—including tryptase, cytokines (IL‐4, IL‐13, IL‐31), NGF, and neuropeptides (substance P, CGRP) that drive feed‐forward loops of neurogenic inflammation and sensory sensitization [1, 5].

The clinical validation of this axis is exemplified by the therapeutic success of biologics targeting IL‐31 and IL‐4/IL‐13 pathways in atopic dermatitis and prurigo nodularis, while emerging strategies including mast cell depletion and suppression (anti‐KIT antibodies and BTK inhibitors), and MRGPRX2 antagonists offer additional precision approaches [73, 76]. The recognition that mast cells and sensory neurons form functional neuroimmune clusters, with MRGPRX2 signalling as a primary communication mechanism, provides a unifying framework for understanding diverse chronic itch and pain conditions [17].

Future advances will depend on translating mechanistic insights from animal models to human disease, developing reliable biomarkers for patient stratification, and designing multi‐target interventions that address the bidirectional nature of mast cell‐neuron communication [4, 6]. As our understanding of this neuroimmune network deepens, precision therapies targeting specific nodes of the mast cell‐neuron axis hold promise for transforming the management of chronic pruritic and pain disorders that have long resisted conventional treatment approaches.

Author Contributions

G.Y. conceptualized the review. T.K. performed the literature search, wrote and revised the manuscript, and prepared the figures. G.Y. supervised and provided critical revisions.

Conflicts of Interest

Dr. Gil Yosipovitch serves as an advisory board member for Arcutis Biotherapeutics, AbbVie, Eli Lilly, Galderma, GSK, Kiniksa Pharmaceuticals, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals Inc., Sanofi, Escient, and Merck Vifor. Dr. Gil Yosipovitch receives grants/research funding from Regeneron Pharmaceuticals Inc. and Sanofi. Dr. Gil Yosipovitch is an investigator for Pfizer, Eli Lilly, Novartis, Escient, and Sanofi. Tomer Kagan has no conflicts of interest to disclose.

Data Availability Statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.