The Role of Mast Cells and Their Potential as a Therapeutic Target For Neuroinflammation

Abstract

Neuroinflammation is increasingly recognized as a central mechanism underlying the onset and progression of numerous neurological disorders, including neurodegenerative, autoimmune, and cerebrovascular diseases. Although microglia and astrocytes are traditionally considered the primary mediators of inflammatory responses within the central nervous system (CNS), accumulating evidence has identified mast cells (MCs) as important contributors to neuroimmune regulation. Strategically located at the interface between the peripheral immune system and the CNS, MCs can rapidly respond to a variety of endogenous and exogenous stimuli through the release of bioactive mediators, including histamine, proteases, cytokines, chemokines, and lipid-derived molecules. These mediators influence blood-brain barrier (BBB) integrity, promote glial activation, modulate neuronal signaling, and contribute to the amplification of inflammatory cascades. Increasing experimental and clinical evidence supports the involvement of MCs in the pathogenesis of several neurological conditions, including Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, migraine, and ischemic brain injury. Consequently, modulation of mast cell activity has emerged as a promising therapeutic approach for limiting neuroinflammatory damage and restoring neuroimmune homeostasis. This review provides an overview of mast cell biology within the CNS, discusses the molecular mechanisms linking MCs to neuroinflammation, examines their contribution to major neurological disorders, and highlights current and emerging therapeutic strategies targeting MCs-mediated pathways. A deeper understanding of mast cell functions in neuroinflammatory processes may facilitate the development of innovative and more effective interventions for neurological diseases.

Introduction

Neuroinflammation is a complex biological response that plays a pivotal role in maintaining central nervous system (CNS) homeostasis under physiological conditions while contributing to the pathogenesis of numerous neurological disorders when dysregulated.¹ Initially regarded as a secondary consequence of neuronal injury, neuroinflammation is now recognized as an active driver of disease progression in a wide spectrum of acute and chronic CNS conditions, including neurodegenerative diseases, autoimmune disorders, cerebrovascular injuries, and traumatic brain damage.¹ Persistent activation of inflammatory pathways can disrupt neuronal function, compromise synaptic integrity, and ultimately exacerbate neurodegeneration, highlighting the need to better understand the cellular and molecular mechanisms underlying neuroinflammatory processes.² The innate immune system represents the first line of defense within the CNS and is essential for tissue surveillance, pathogen recognition, and the orchestration of inflammatory responses.³ Among the various cellular components involved, microglia have long been considered the principal immune effector cells of the brain.⁴ Together with astrocytes, these cells regulate immune signaling, maintain tissue homeostasis, and respond to injury through the production of cytokines, chemokines, and other inflammatory mediators.⁴ However, increasing evidence indicates that neuroinflammation results from the coordinated interaction of multiple immune and non-immune cell populations, extending beyond the traditional microglia-centered paradigm.⁵

In recent years, Mast Cells (MCs) have emerged as important regulators of neuroimmune communication. Although historically associated with allergic reactions and peripheral inflammatory responses, MCs are now recognized as multifunctional immune cells capable of influencing both physiological and pathological processes within the CNS.⁶ Their strategic localization in the meninges, perivascular spaces, and regions adjacent to the blood-brain barrier (BBB) enables them to rapidly respond to environmental, immunological, and neuronal stimuli.⁷ Upon activation, MCs release a broad repertoire of preformed and newly synthesized mediators, including histamine, proteases, cytokines, growth factors, and lipid-derived molecules, which can profoundly affect BBB permeability, glial activation, neuronal signaling, and leukocyte recruitment.⁷

Accumulating experimental and clinical findings suggest that MCs may participate in early neuroinflammatory responses and contribute to the subsequent amplification of inflammation in several neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), migraine, stroke, and traumatic brain injury (TBI).^8,9 Furthermore, growing evidence supports the existence of bidirectional interactions between MCs and resident CNS cells, particularly microglia and astrocytes. However, the extent and functional relevance of these interactions vary according to the experimental model and disease context, and some proposed mechanisms remain inferential rather than directly demonstrated.¹⁰ Despite these advances, the precise mechanisms through which MCs modulate neuroinflammation remain incompletely understood, and their potential as therapeutic targets has yet to be fully explored.

Although numerous studies have investigated individual aspects of MCs biology in neurological diseases, a comprehensive understanding of their role in neuroinflammation and the therapeutic implications of targeting MCs-mediated pathways is still lacking. Bridging this knowledge gap is essential for identifying novel strategies capable of modulating detrimental inflammatory responses while preserving physiological immune functions within the CNS.

Therefore, this review aims to summarize current knowledge regarding mast cell biology in the CNS, examine the molecular mechanisms linking MCs to neuroinflammatory processes, discuss their involvement in major neurological disorders, and evaluate existing and emerging therapeutic approaches targeting mast cell activity. By integrating recent experimental and clinical evidence, this review seeks to provide a comprehensive overview of the contribution of MCs to neuroinflammation and their potential as promising therapeutic targets in neurological diseases.

Biology of MCs

Origin and Differentiation

MCs are long-lived tissue-resident immune cells that play essential roles in host defense, tissue homeostasis, allergic reactions, and chronic inflammatory diseases.¹¹ Unlike many other mature immune cells, MCs do not complete their differentiation within the bone marrow. In fact, although they originate from hematopoietic progenitors, they then leave the bone marrow as immature cells and undergo terminal maturation only after reaching peripheral tissues.¹² This distinctive developmental pathway allows MCs to adapt to local microenvironmental signals and contributes to their remarkable phenotypic and functional heterogeneity.¹³

Hematopoiesis

Mast cell ontogeny begins in the bone marrow from hematopoietic stem cells (HSCs), which possess self-renewal capacity and the ability to generate all blood cell lineages.^12,14 HSCs differentiate into multipotent progenitors and subsequently into common myeloid progenitors (CMPs), giving rise to several myeloid cell populations, including granulocytes, monocytes, and MCs. Further lineage commitment leads to granulocyte–monocyte progenitors (GMPs) and mast cell progenitors (MCPs), which progressively acquire mast cell-specific characteristics while maintaining an immature phenotype. Mast cell progenitors are typically characterized by the expression of CD34, the receptor for stem cell factor (SCF), which represents the principal growth and survival signal for MCs.^12,14 In contrast to basophils and other granulocytes that complete their maturation within the bone marrow, mast cell progenitors enter the circulation as immature cells and subsequently migrate to peripheral tissues. Their recruitment and tissue homing are regulated by adhesion molecules, integrins, and chemokine receptors that facilitate migration under both physiological and inflammatory conditions.¹⁴

Tissue Maturation

Once they reach peripheral tissues, including the skin, respiratory tract, and gastrointestinal mucosa, MCs undergo terminal differentiation. Their maturation is strongly influenced by the local microenvironment, particularly by SCF, cytokines, and interactions with stromal cells, fibroblasts, and extracellular matrix components. As a consequence, mature MCs become permanently resident within tissues, where they acquire specialized phenotypic and functional characteristics.¹⁵ The molecular mechanisms governing mast cell differentiation involve a complex network of transcription factors that regulate both lineage commitment and terminal maturation. Members of the GATA family, particularly GATA1 and GATA2, play crucial roles during mast cell development.¹⁵ Studies by Migliaccio¹⁶ and Ghinassi¹⁷ demonstrated that mice lacking the first enhancer and distal promoter of GATA1 exhibit defects in mast cell development. These investigations identified a common progenitor with erythroid, megakaryocytic, and mast cell potential, indicating that GATA1 plays a critical role during early mast cell lineage commitment. In addition to GATA factors, other transcriptional regulators, including MITF, PU.1, and STAT5, contribute to mast cell differentiation, survival, and functional maturation. The Notch signaling pathway has also emerged as an important regulator of mast cell development.¹⁸ Sakata-Yanagimoto et al^18,19 investigated the effects of Notch receptor signaling, which is known to influence the differentiation of multiple hematopoietic lineages, including T cells and marginal zone B cells. MCs express high levels of Notch2, suggesting a possible role for this pathway in mast cell commitment. Using a Delta1-Fc chimeric protein, a ligand of the Notch receptor, the authors cultured CMPs and GMPs in the presence of stem cell factor and IL-3. Activation of Notch signaling promoted the generation of cultures highly enriched in MCs, whereas control cultures predominantly differentiated into granulocytes and macrophages. These findings indicate that Notch signaling may favor mast cell lineage commitment by directing myeloid progenitors toward mast cell differentiation.¹⁸ Overall, mast cell development is regulated by a coordinated interplay between hematopoietic lineage commitment, tissue-specific maturation signals, and transcriptional programs. This multistep process ultimately generates highly specialized tissue-resident cells characterized by substantial phenotypic and functional diversity.

MCs Heterogeneity

A distinctive feature of MCs is their remarkable phenotypic and functional heterogeneity, which largely arises from their tissue-dependent maturation and the influence of local microenvironmental signals.²⁰ Since mast cell progenitors complete their differentiation after migrating to peripheral tissues, factors such as cytokines, growth factors, extracellular matrix components, and interactions with neighboring cells contribute to the acquisition of tissue-specific characteristics.²¹ Consequently, MCs exhibit a high degree of plasticity, allowing them to adapt their phenotype and function according to the local environment and the nature of the stimuli they encounter. Changes in mast cell phenotype may occur throughout virtually all stages of their lifespan. Their widespread distribution across different tissues and their continuous exposure to pathogens, allergens, inflammatory mediators, and environmental signals contribute to the generation of distinct mast cell populations with specific structural, biochemical, and functional properties. This diversity underlies the broad range of physiological and pathological responses mediated by MCs. Human MCs have traditionally been classified into two major subsets according to their protease content. The mast cell tryptase/chymase (MC_TC) subtype contains tryptase, chymase, and carboxypeptidase A3 within its cytoplasmic granules, whereas the mast cell tryptase (MC_T) subtype predominantly stores tryptase.²¹ In addition to proteases, human MCs contain serglycin proteoglycans composed of both heparin and chondroitin sulfate, which contribute to granule organization and mediator storage. The distribution of these subsets varies according to tissue localization. MC_T cells are predominantly found within the intestinal and pulmonary mucosa, often in close proximity to T lymphocytes, whereas MC_TC cells are mainly localized in the skin, lymph nodes, and the submucosal regions of the gastrointestinal and respiratory tracts.²¹ More recently, additional mast cell phenotypes have been identified. A subset expressing tryptase and carboxypeptidase A3, but lacking chymase expression, has been described in the airway epithelium of asthmatic patients and in esophageal tissues from individuals with eosinophilic esophagitis, suggesting that mast cell diversity extends beyond the classical binary classification.

MCs heterogeneity is further reflected by differences in receptor expression, activation thresholds, mediator content, and secretory responses.²² Variations in the repertoire of stored and newly synthesized mediators, including histamine, proteases, cytokines, chemokines, and lipid mediators, determine the wide range of biological functions that MCs can exert in different tissues. Throughout their lifespan, MCs remain highly responsive to environmental cues, and the dynamic modulation of their phenotype may ultimately influence whether they contribute to tissue homeostasis or to the development of pathological conditions such as allergy, chronic inflammation, fibrosis, and cancer.²³

MCs Mediators

MCs are highly specialized secretory cells that exert their biological functions through the release of a broad spectrum of mediators.²⁴ Upon activation, MCs can rapidly release preformed mediators stored within cytoplasmic granules and subsequently synthesize de novo a variety of lipid mediators, cytokines, and chemokines.²⁴ Preformed mediators are stored within cytoplasmic granules and can be rapidly released through degranulation within seconds or minutes after mast cell activation. These mediators are responsible for the early phase of mast cell responses and contribute to vascular, inflammatory, and immunomodulatory effects.⁶

Histamine

It is one of the best-characterized mast cell mediators and is responsible for many of the classical manifestations of allergic reactions.²⁵ Through binding to histamine receptors (H1–H4), histamine induces vasodilation, increased vascular permeability, smooth muscle contraction, mucus secretion, and sensory nerve stimulation, leading to symptoms such as edema, bronchoconstriction, pruritus, and hypotension.²⁶

Tryptase and Chymase

Mast cell granules also contain large amounts of neutral proteases, including tryptase and chymase.²⁷ Tryptase is the most abundant mast cell protease and serves as a widely used biomarker of mast cell activation. It contributes to extracellular matrix remodeling, leukocyte recruitment, and activation of protease-activated receptors. Chymase participates in tissue remodeling, matrix degradation, angiogenesis, and the generation of angiotensin II, thereby influencing both inflammatory and cardiovascular processes.

Cytokines and Chemokines

Another important preformed mediator is TNF-α, which can be stored within granules and rapidly released after activation. TNF-α promotes endothelial activation, leukocyte recruitment, and the amplification of inflammatory responses, thereby linking mast cell activation to both innate and adaptive immunity. Following activation, MCs initiate de novo synthesis of numerous inflammatory mediators.²⁸ Unlike preformed mediators, these molecules are generated after stimulation and contribute to the late-phase inflammatory response. MCs produce a wide array of cytokines, including TNF-α, IL-1β, IL-4, IL-5, IL-6, IL-9, IL-13, IL-17, and transforming growth factor-β (TGF-β). These cytokines regulate the recruitment, differentiation, and activation of immune cells and influence both pro-inflammatory and immunoregulatory responses.⁶ MCs secrete numerous chemokines, such as CCL2, CCL3, CCL5, CXCL8, and CXCL10, which direct the migration of neutrophils, eosinophils, monocytes, T lymphocytes, and other immune cells to sites of inflammation.⁶ Activated MCs also rapidly generate eicosanoids through the metabolism of arachidonic acid. These lipid mediators include prostaglandin D2 (PGD2), leukotriene C4 (LTC4), leukotriene D4 (LTD4), and leukotriene E4 (LTE4). Eicosanoids contribute to bronchoconstriction, vascular permeability, mucus secretion, leukocyte recruitment, and tissue inflammation.²⁹

Activation Pathways of MCs

MCs can be activated through multiple receptor-mediated pathways, allowing them to respond to allergens, pathogens, endogenous danger signals, and neuroimmune stimuli.³⁰

IgE-Dependent Activation

The classical mechanism of mast cell activation involves the high-affinity receptor for immunoglobulin E (FcεRI).²⁶ IgE molecules bind FcεRI on the mast cell surface. Subsequent cross-linking of receptor-bound IgE by multivalent antigens triggers intracellular signaling cascades, ultimately resulting in degranulation and mediator release. IgE-dependent activation is responsible for immediate hypersensitivity reactions, including allergic rhinitis, asthma, urticaria, food allergy, and anaphylaxis. In addition to degranulation, FcεRI signaling induces the synthesis of cytokines, chemokines, and lipid mediators that sustain the late-phase allergic response.³¹

Toll-Like Receptors (TLRs)

MCs express several TLRs, including TLR2, TLR4, TLR7, and TLR9, which recognize pathogen-associated molecular patterns (PAMPs) derived from bacteria, viruses, fungi, and parasites. TLRs activation generally promote cytokine and chemokine production and may occur independently of degranulation. Through TLRs signaling, MCs contribute to innate immune responses by promoting pathogen clearance, recruiting immune cells, and modulating adaptive immunity.

Danger-Associated Molecular Patterns (DAMPs)

MCs also recognize endogenous danger signals released during cellular stress, tissue injury, or necrosis. These DAMPs, including high-mobility group box 1 (HMGB1), ATP, heat-shock proteins, and extracellular nucleic acids, activate MCs through pattern-recognition receptors. DAMPs-mediated activation allows MCs to respond rapidly to sterile tissue damage and contributes to wound healing, tissue repair, and inflammatory responses.

Neurogenic Stimuli

Bidirectional communication between MCs and the nervous system represents an important mechanism of neuroimmune regulation. MCs express receptors for several neuropeptides, including substance P, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), and neurotensin. Neurogenic stimulation can induce mast cell degranulation and cytokine production, thereby contributing to pain, pruritus, neurogenic inflammation, and stress-related inflammatory disorders.

In addition to physiological receptor-mediated activation, MCs may undergo dysregulated or constitutive activation in pathological conditions. Mast cell activation syndrome (MCAS) encompasses a heterogeneous group of disorders characterized by recurrent systemic episodes of excessive mast cell mediator release. In primary or clonal MCAS, activating abnormalities of KIT, particularly the KIT D816V mutation, can promote ligand-independent signaling and increased mast cell activation.³² By contrast, secondary MCAS is generally driven by IgE-dependent or other immunological stimuli without an underlying clonal mast cell disorder, whereas in idiopathic MCAS no specific trigger or clonal abnormality is identified. These different mechanisms highlight that mast cell activation may result from both external stimuli and intrinsic alterations in mast cell signaling.

All processes described in Biology of MCs are summarized in Figure 1.

Figure 1.

Development, Tissue Maturation, and Phenotypic Heterogeneity of MCs. Overview of mast cell (MC) origin, differentiation, tissue maturation, and heterogeneity. MCs arise from hematopoietic progenitors in the bone marrow, migrate as immature progenitors to peripheral tissues, and complete their maturation under the influence of SCF/c-Kit signaling and local microenvironmental cues. Tissue-specific signals shape MCs functional plasticity and determine distinct phenotypes, including the different human MCs subsets.

The Role of MCs in the CNS

Although MCs are traditionally recognized as peripheral immune cells, increasing evidence indicates that they also reside within the CNS, where they contribute to neuroimmune communication and the regulation of neuroinflammatory processes.⁷ Owing to their strategic localization at the interface between the immune, vascular, and nervous systems, MCs are able to respond rapidly to both peripheral and central stimuli. Their ability to release a wide array of mediators enables them to influence BBB integrity, vascular function, glial activation, and neuronal activity, thereby contributing to both physiological homeostasis and neurological disease.⁷

Localization in the CNS and Meninges

MCs are strategically located in close proximity to neurons within both the peripheral and CNS, suggesting an important role in neuroimmune communication under physiological conditions as well as in neuroinflammatory and neurodegenerative disorders. Their intimate anatomical association with nerve fibers enables bidirectional interactions that influence neuronal activity, immune responses, and tissue homeostasis.³³ Notably, MCs share several functional characteristics with neurons, including the expression of monoaminergic systems, responsiveness to neuropeptides and neurotrophins, and the capacity to synthesize and release a variety of neuroactive and neurotrophic mediators.³³ Studies investigating rodent brain development indicate that MCs first emerge during late embryonic and early postnatal stages within the pia mater, choroid fissure, choroid plexus, cerebral cortex, and peri-hippocampal regions, particularly along the margins of the choroid fissure, a ventricular extension located adjacent to the developing hippocampus.³⁴ These anatomical regions are thought to represent potential gateways for the migration of circulating mast cell progenitors from the peripheral circulation into the developing brain. Their accessibility may be explained by the incomplete maturation of the BBB during early developmental stages, which facilitates the entry and colonization of mast cell precursors within the CNS.^35,36 In humans, MCs have been identified predominantly within the meninges and in perivascular regions associated with circumventricular organs (CVOs), including the median eminence, pineal gland, area postrema, and subfornical organ, where the BBB is relatively permissive.⁷ Evidence supporting a substantial population of MCs within the human hypothalamic or thalamic parenchyma remains limited.⁷ In rodent studies, MCs have been reported more frequently at hypothalamic borders and in association with ventricular, meningeal, and perivascular structures rather than being uniformly distributed throughout the hypothalamic parenchyma.⁷ Similarly, MCs described in relation to the thalamus are more commonly localized along thalamic borders and structures associated with the ventricular system, including the velum interpositum.³⁷ These anatomical distinctions are important when interpreting the potential contribution of MCs to neuroimmune regulation within the CNS.

Interaction of MCs with the BBB

The BBB is a highly specialized structure that regulates the exchange of molecules and cells between the circulation and the CNS. MCs are strategically positioned near cerebral blood vessels and can profoundly influence BBB integrity through the release of multiple mediators.⁷ One of the principal consequences of mast cell activation is the increase in BBB permeability. Histamine, tryptase, and other inflammatory mediators can alter endothelial cell function and increase vascular leakage.⁷ This enhanced permeability facilitates the infiltration of immune cells and circulating molecules into the CNS.³⁸ In particular, mast cell-derived mediators such as prostaglandins and TNF-α have been shown to alter endothelial transcriptional programs, resulting in upregulation of adhesion molecules including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). These adhesion molecules are critical for leukocyte adhesion to the endothelium and subsequent transmigration into the CNS, especially neutrophils.³⁹ Additional mast cell-derived proteases, including chymase and tryptase, contribute to BBB dysfunction. Tryptase promotes the expression of VCAM-1 in brain endothelial cells and disrupts tight junction proteins, such as claudins and occludin, through activation of protease-activated receptor-2 (PAR2).⁴⁰ Furthermore, MCs can directly or indirectly stimulate the release of matrix metalloproteinases, particularly MMP-2 and MMP-9, whose activation contributes to extracellular matrix degradation and increased BBB permeability.

Crosstalk with Glial Cells

MCs actively communicate with resident CNS cells, including microglia, astrocytes, and neurons. This bidirectional crosstalk plays an important role in neuroimmune regulation and may contribute to both physiological and pathological processes.¹⁰ Microglia are the resident immune cells of the CNS and represent one of the primary cellular targets of mast cell mediators. Histamine, tryptase, TNF-α, IL-1β, and other mast cell-derived factors can activate microglia and promote the production of pro-inflammatory cytokines. Conversely, activated microglia release mediators capable of stimulating MCs, creating a positive feedback loop that may amplify neuroinflammation.¹⁰ Astrocytes are essential for maintaining CNS homeostasis, regulating synaptic activity, and supporting BBB integrity. MCs residing in the white matter can induce both morphological and functional changes in astrocytes through the release of proteases and other inflammatory mediators.⁴¹ In particular, mast cell-derived proteases stimulate the production of IL-33 by astrocytes through the activation of intracellular signaling pathways, including p38 and ERK1/2 MAPKs as well as NF-κB.⁴¹ Activation of these pathways promotes astrocyte reactivity and enhances their inflammatory response, thereby contributing to neuroinflammation.

MCs and neurons establish bidirectional interactions through adhesion molecules, including CADM1 and N-cadherin, which facilitate cell-to-cell communication and the formation of synapse-like contacts.⁴² MCs can influence neuronal function through transgranulation, transferring granule components such as heparin that may alter neuronal calcium homeostasis and activity.⁴³ Conversely, neurons regulate mast cell activation by releasing neuropeptides and neurotrophic factors, including substance P, calcitonin gene-related peptide (CGRP), neurotensin (NT), and nerve growth factor (NGF) which in turn promote the release of mast cell-derived cytokines and chemokines, contributing to neuroimmune signaling and neuroinflammatory responses.⁴⁴ Overall, the strategic localization of MCs within the CNS and their interactions with the BBB, glial cells, and neurons supporting their potential role as modulators of neuroinflammation and neuroimmune communication.

Figure 2 provides a schematic overview of the localization of MCs in the CNS and the principal cellular and molecular mechanisms underlying their contribution to neuroinflammation.

Figure 2.

Localization of MCs in the CNS and Their Interactions with the BBB and Neural Cells. Schematic representation of MCs localization at CNS interfaces, including meninges, perivascular regions, and circumventricular organs. MC-derived mediators can modulate BBB integrity and interact with microglia, astrocytes, and neurons, thereby contributing to neuroimmune communication and neuroinflammatory responses.

Molecular Mechanisms Linking MCs to Neuroinflammation

MCs are increasingly recognized as potential contributors to neuroinflammatory processes through their ability to respond to diverse stimuli and release a wide range of bioactive mediators. Experimental studies using CNS-relevant cellular and animal models support effects of mast cell-derived mediators on BBB integrity, glial activation, and neuroimmune signaling. However, several proposed mechanisms, particularly those involving cytokine, oxidative, and neuroactive signaling pathways, have been inferred from studies of peripheral MCs or in vitro systems and have not yet been fully demonstrated for brain-associated or meningeal MCs in vivo. Therefore, the following sections distinguish, where possible, between experimentally supported CNS-related effects and mechanisms that remain proposed or extrapolated from non-CNS models.

Cytokine Signaling

A key mechanism through which MCs contribute to neuroinflammation is the production and release of cytokines that regulate immune cell recruitment, glial activation, and neuronal function. Following stimulation by pathogens, damage-associated molecular patterns (DAMPs), neuropeptides, or stress-related signals, MCs rapidly secrete a broad repertoire of pro-inflammatory mediators, establishing a local inflammatory milieu that can profoundly influence CNS.⁴⁵ Among these mediators, IL-1β, IL-6, and TNF-α represent major drivers of neuroinflammatory signaling and are critically involved in the crosstalk between MCs and resident CNS cells.⁴⁶

Rather than acting independently, these cytokines form a tightly interconnected network that amplifies inflammatory responses. TNF-α, one of the earliest mediators released following mast cell activation, promotes endothelial activation, increases the expression of adhesion molecules, and facilitates leukocyte trafficking across the BBB.⁶ Simultaneously, TNF-α stimulates microglia and astrocytes, inducing the production of additional inflammatory mediators that further sustain local immune activation.⁶ IL-1β exerts complementary effects by enhancing glial reactivity, promoting the expression of pro-inflammatory genes, and contributing to BBB dysfunction.⁴⁷ Moreover, IL-1β can directly influence neuronal activity, altering synaptic plasticity and neurotransmission while fostering a microenvironment conducive to chronic inflammation.⁴⁷

IL-6 further strengthens these processes through the activation of intracellular signaling pathways such as JAK/STAT, which regulate the expression of genes involved in immune cell survival, differentiation, and cytokine production.⁴⁸ Although transient IL-6 signaling may contribute to tissue repair and neuroprotection, persistent elevation of this cytokine is frequently associated with chronic neuroinflammation and progressive neuronal dysfunction.⁴⁹ Importantly, IL-6 can also potentiate the activation of microglia and astrocytes, thereby reinforcing the inflammatory loop initiated by mast cell-derived mediators.⁵⁰

Beyond these canonical cytokines, MCs produce several chemokines and growth factors, including CCL2, CXCL8, and GM-CSF, which contribute to the recruitment and activation of peripheral immune cells.⁵¹ Indeed, depending on the activating stimulus and tissue context, MCs can also produce chemokines and growth factors such as CCL2, CXCL8, and GM-CSF.⁵² For example, FcεRI-mediated activation of human MCs induces CCL2 and CXCL8 expression and secretion, whereas IgE-dependent stimulation has been shown to promote GM-CSF production in human lung MCs.⁵² However, these observations largely derive from peripheral or in vitro mast cell systems, and direct evidence demonstrating comparable production by brain-associated or meningeal MCs in vivo remains limited.⁵³ Therefore, their contribution to CNS neuroinflammation should currently be regarded as plausible but not definitively established.

This cytokine-rich environment facilitates bidirectional communication between peripheral and central immune compartments, promoting the persistence of inflammatory responses. Collectively, mast cell-derived cytokines act in concert to disrupt neuroimmune homeostasis, amplify glial activation, and sustain the chronic inflammatory processes that characterize many neurological disorders.

Oxidative Stress and reactive oxygen species (ROS) Generation

Oxidative stress represents another major mechanism through which MCs contribute to neuroinflammation and neuronal dysfunction.⁹ Under physiological conditions, ROS are generated at low levels and participate in cellular signaling, immune surveillance, and tissue homeostasis.⁵⁴ However, excessive ROS production can overwhelm endogenous antioxidant defenses, leading to oxidative damage of lipids, proteins, and nucleic acids.⁵⁴ Increasing evidence suggests that MCs play an important role in this process by both generating ROS directly and promoting oxidative stress through the release of pro-inflammatory mediators.⁵⁴

Upon activation, MCs undergo metabolic and signaling changes that stimulate the production of ROS through multiple pathways, including mitochondrial activity and the activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases.⁵⁵ In addition, mast cell-derived cytokines, such as TNF-α and IL-1β, can enhance ROS generation in neighboring microglia, astrocytes, and endothelial cells, amplifying oxidative damage within the CNS.⁹ This creates a self-reinforcing cycle in which inflammation promotes oxidative stress, while oxidative stress further potentiates inflammatory signaling.

ROS-mediated damage has important consequences for neuroimmune homeostasis.⁹ Excessive oxidative stress can impair BBB integrity by disrupting endothelial tight junctions, thereby facilitating the infiltration of peripheral immune cells into the CNS.⁹ Furthermore, ROS activate redox-sensitive signaling pathways, including nuclear factor-kappa B (NF-κB), which drives the expression of numerous pro-inflammatory genes and contributes to the persistence of neuroinflammatory responses.⁵⁶ Oxidative stress also promotes microglial activation and astrocyte reactivity, enhancing the production of inflammatory mediators that further exacerbate tissue injury.⁵⁷

Neurons are particularly vulnerable to oxidative damage because of their high metabolic demand and limited antioxidant capacity.⁵⁷ Consequently, prolonged exposure to ROS can result in mitochondrial dysfunction, impaired synaptic transmission, and ultimately neuronal death.⁵⁷ These mechanisms have been implicated in the pathogenesis of several neurodegenerative and neuroinflammatory disorders, including AD, PD, MS, and ischemic brain injury. By acting both as sources and amplifiers of oxidative stress, MCs contribute to the establishment of a pro-oxidative and pro-inflammatory environment that favors disease progression.

MCs in Neurological Disorders

The mechanisms described above suggest that MCs may influence neurological disease progression through multiple, partially overlapping pathways, including BBB dysfunction, glial activation, cytokine release, oxidative stress, neurogenic inflammation, and peripheral-central immune communication. Rather than acting as isolated effector cells, MCs appear to function as amplifiers of neuroimmune signaling, particularly in pathological contexts characterized by chronic inflammation or barrier disruption. Their involvement has been investigated in several neurological disorders, ranging from autoimmune demyelinating diseases to neurodegenerative conditions and pain-related syndromes. Although the strength of evidence varies across disease models, available data support the concept that MCs activation can contribute to disease-specific processes such as demyelination, amyloid-related inflammation, αSyn-driven neurotoxicity, meningeal sensitization, and peripheral nociceptive amplification. The following sections discuss the current evidence linking MCs to major neurological disorders, highlighting both shared mechanisms and disease-specific features.

Relationship Between MCs and MS

MS is a chronic autoimmune and neurodegenerative disorder characterized by inflammatory demyelination and progressive axonal damage within the CNS.⁵⁸ Although adaptive immune responses have traditionally been considered the major drivers of disease pathogenesis, increasing evidence supports a significant contribution of innate immune cells, including MCs, particularly during the early phases of neuroinflammation.⁵⁸ MCs have been identified in active MS lesions and in perivascular areas, where their strategic localization places them at the interface between peripheral immune cells and the CNS microenvironment.⁵⁹

Insights into the contribution of MCs to MS have largely emerged from experimental autoimmune encephalomyelitis (EAE), the most widely used animal model of the disease. Early studies demonstrated that MC-deficient mice exhibit delayed disease onset and reduced severity, suggesting a pathogenic role for these cells.⁶⁰ However, subsequent investigations using alternative models yielded more complex and sometimes contradictory findings, indicating that the contribution of MCs may depend on disease stage, experimental conditions, and interactions with other immune populations.^61,62 Despite these discrepancies, EAE studies consistently support the concept that MCs participate in shaping both peripheral and central inflammatory responses.^63,64

One of the earliest events in MS pathogenesis is the disruption of BBB integrity, which facilitates the entry of autoreactive lymphocytes and inflammatory mediators into the CNS.⁶⁵ Activated MCs contribute to this process through the release of histamine, TNF-α, proteases, and matrix metalloproteinases, which alter endothelial tight junctions and promote leukocyte extravasation.⁶⁶ In addition, MC-derived mediators enhance microglial activation and amplify local inflammatory signaling, thereby creating a permissive environment for immune cell infiltration and lesion development.⁶⁶

Beyond BBB dysfunction, MCs have also been proposed to contribute to demyelinating processes. Inflammatory mediators released by activated MCs, including cytokines, ROS, and proteases, may create a microenvironment that is detrimental to oligodendrocyte function and myelin integrity. However, direct evidence demonstrating mast cell-mediated oligodendrocyte injury or myelin damage remains limited, and this mechanism should therefore be regarded as plausible rather than definitively established.

Elevated levels of MCs-associated mediators, including tryptase, have been detected in the cerebrospinal fluid of patients during active disease phases, supporting their involvement in ongoing inflammatory activity.⁶⁷ Moreover, growing evidence suggests that MCs may influence adaptive immune responses by modulating Th1 and Th17 polarization, thereby contributing to the persistence of autoimmune inflammation.⁶⁷

Although the precise role of MCs in MS remains incompletely understood, available evidence supports their involvement in BBB disruption, immune cell recruitment, and demyelination. These observations have raised interest in MC-targeted therapeutic approaches, which may complement current immunomodulatory strategies by limiting neuroinflammatory amplification and preserving CNS homeostasis.

The Influence of MCs During AD Establishment and Progression

AD is the most common cause of dementia and is characterized by progressive cognitive decline associated with extracellular amyloid-β (Aβ) deposition, intracellular tau pathology, synaptic dysfunction, and chronic neuroinflammation.⁶⁸

While microglia have long been regarded as the primary immune cells involved in AD pathogenesis, increasing evidence suggests that MCs may also contribute to disease progression by acting as early sensors and amplifiers of inflammatory responses.⁶⁹

MCs are strategically localized near cerebral blood vessels and meningeal structures, where they are well positioned to respond to Aβ accumulation and other danger-associated signals.⁷⁰ Scientific evidence indicates that Aβ peptides can activate MCs, although the available findings derive from different experimental systems. Niederhoffer et al showed that fibrillar Aβ1-40 and Aβ1-42 induced exocytosis and phagocytic responses in rat peritoneal MCs through a CD47/β1-integrin-dependent mechanism.⁷¹ Harcha et al subsequently demonstrated Aβ25-35-induced MCs degranulation in cultured MCs and acute mouse brain slices, involving pannexin-1 and connexin-43 hemichannels.⁷² More recently, Liu et al reported that Aβ1-42, Aβ1-40, and Aβ25-35 promoted inflammatory mediator release from human LADR MCs cultured in a three-dimensional collagen-based system.⁷³ Collectively, these findings support a direct capacity of Aβ peptides to activate MCs; however, evidence demonstrating this mechanism specifically in human brain-resident MCs in vivo remains limited.

The reciprocal interaction between MCs and microglia has emerged as a critical component of AD-associated neuroinflammation.⁴⁵ MC-derived mediators can enhance microglial reactivity and stimulate the production of pro-inflammatory cytokines and ROS, thereby contributing to a persistent inflammatory milieu.⁷⁴ Conversely, activated microglia further amplify MCs responses, creating a self-sustaining cycle of neuroimmune activation.⁷⁴ This interplay has been implicated in synaptic impairment and progressive neuronal loss, both of which are strongly associated with cognitive decline.⁷⁴

In addition to their effects on glial cells, MCs may influence disease progression through vascular mechanisms.⁶ Increased BBB permeability and dysfunction of the neurovascular unit are recognized features of AD and may facilitate the infiltration of peripheral immune cells and inflammatory mediators into the CNS.⁷⁵ Through the release of proteases and vasoactive molecules, MCs can contribute to these alterations, thereby linking peripheral inflammation with central neurodegenerative processes.⁷⁶

Evidence from transgenic mouse models and human studies further supports the involvement of MCs in AD pathology.^74,77 Increased numbers of activated MCs and elevated levels of mast cell-associated mediators have been detected in brain tissues and cerebrospinal fluid from AD patients.⁷⁸ Moreover, pharmacological interventions aimed at stabilizing MCs or attenuating their inflammatory responses such as palmitoylethanolamide (PEA) have shown beneficial effects in experimental models, suggesting that modulation of MCs activity may represent a promising strategy for limiting neuroinflammation and slowing disease progression.^79,80 Although further studies are required to clarify the precise contribution of MCs to AD, current findings support their role as active participants in the complex network of neuroimmune interactions underlying cognitive decline.

The Role of MCs in PD

PD is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta and by the accumulation of misfolded α-syn aggregates, which ultimately form Lewy bodies.^81,82 Although traditionally considered a neuronal disorder, increasing evidence supports a substantial contribution of neuroinflammatory mechanisms to disease progression.^81,83 In this context, MCs have emerged as potential modulators of neuroinflammatory signaling; however, their specific contribution to PD remains less clearly established than that of microglia and astrocytes, and much of the available evidence derives from experimental models rather than human PD brain tissue.

Literature data suggest that MCs can directly respond to PD-relevant stimuli. Kempuraj et al demonstrated that α-syn and the dopaminergic neurotoxin MPP⁺ activate mouse bone marrow-derived MCs and human umbilical cord blood-derived MCs, promoting degranulation and the release of inflammatory mediators.⁸⁴ Subsequent studies using MCs-glia/neuron co-culture systems further showed that MPP⁺ and MCs-derived proteases can enhance inflammatory signaling in astrocytes and neurons.⁸⁵ Importantly, studies in MPTP-treated mice also reported lower brain levels of IL-1β, TNF-α, and CCL2 in MCs-deficient animals compared with wild-type mice, providing in vivo evidence that MCs may contribute to the amplification of neuroinflammatory responses.⁴⁴ Nevertheless, these findings do not establish resident brain MCs as primary initiators of PD pathology, and mast cell-glial communication is more appropriately considered a potential secondary amplification mechanism.

A distinct issue concerns the potential involvement of MCs in the gut-brain axis. Intestinal MCs are abundant at mucosal interfaces and can respond to microbial products, dysbiosis-associated signals, and local inflammatory stimuli, potentially contributing to intestinal barrier dysfunction and systemic inflammation.⁸⁶ These cells should, however, be distinguished from meningeal and perivascular MC populations associated with the CNS.⁸⁷ Current evidence does not demonstrate that these populations constitute a single continuous mast cell pathway in PD;⁸⁸ rather, anatomically distinct MC populations may amplify inflammatory signaling locally at the peripheral and central ends of the gut–brain axis. Moreover, direct evidence for substantial recruitment of MCs progenitors into the PD brain remains limited.

These findings support a potential role for MCs as secondary amplifiers of PD-associated neuroinflammation rather than established primary drivers of the disease. Further studies using human tissue and models capable of distinguishing CNS-associated, peripheral, and intestinal MC populations are required to define their contribution to PD progression.

Migraine and Headache Disorders: The Involvement of MCs in These Pathological Conditions

Among neurological disorders, migraine represents one of the conditions in which the contribution of MCs has been most extensively investigated. Increasing evidence indicates that migraine is not solely a vascular or neuronal disorder but rather a complex neuroimmune disease involving bidirectional communication between meningeal immune cells and the trigeminovascular system.⁸⁹ Due to their close anatomical proximity to sensory nerve endings and blood vessels within the dura mater, MCs are strategically positioned to participate in the initiation and amplification of headache-associated neuroinflammatory responses.⁹⁰

Activation of meningeal MCs leads to the release of histamine, tryptase, prostaglandins, cytokines, and other pro-inflammatory mediators capable of sensitizing trigeminal afferents and promoting vasodilation.⁹¹ In turn, activated trigeminal fibers release neuropeptides such as CGRP, SP, and PACAP, establishing a reciprocal interaction that sustains neurogenic inflammation.⁹² This bidirectional communication creates a self-amplifying cycle in which neuronal activation promotes MCs degranulation, while MC-derived mediators further enhance nociceptor excitability and inflammatory signaling.⁹²

Among these mediators, it is well known that CGRP is a key player in migraine.⁹³ Released from trigeminal nerve endings during migraine attacks, CGRP contributes to vasodilation, plasma protein extravasation, and nociceptive transmission.⁹⁴ Experimental studies have demonstrated that elevated CGRP levels may promote MCs activation and histamine release, whereas MC-derived inflammatory mediators can further stimulate trigeminal neurons, thereby perpetuating the inflammatory cascade.⁹⁵ This reciprocal relationship between MCs and CGRP signaling is consistent with the clinical efficacy of CGRP-targeting therapies and underscores the importance of neuroimmune mechanisms in migraine.⁹⁶

Beyond acute attacks, persistent activation of meningeal MCs may contribute to central sensitization and the transition from episodic to chronic migraine.⁹⁷ Altered cytokine profiles, oxidative stress, and sustained glial activation have all been implicated in this process, suggesting that chronic neuroinflammation may represent a common denominator linking recurrent headaches with long-term changes in pain processing. Similar mast cell-associated neurogenic inflammatory mechanisms have also been proposed in cluster headache, although the available evidence is substantially more limited than in migraine.⁹⁸

Therefore, the intimate interplay between MCs and the trigeminovascular system highlights the importance of neuroimmune communication in headache disorders. The growing understanding of MC-mediated mechanisms has not only provided new insights into migraine pathogenesis but has also opened novel therapeutic perspectives aimed at modulating neuroinflammatory signaling and interrupting the vicious cycle linking meningeal inflammation to pain generation.

As illustrated in Figure 3, MCs contribute to the pathogenesis of multiple neurological disorders through common neuroinflammatory mechanisms, while also participating in disease-specific pathogenic processes.

Figure 3.

Shared and Disease-Specific Mechanisms of MCs-Mediated Neuroinflammation in Major Neurological Disorders. Overview of the involvement of MCs in MS, AD, PD, and migraine. MCs activation may contribute to common neuroinflammatory mechanisms, including BBB dysfunction, cytokine and protease release, microglial activation, and neuroinflammation, while also participating in disease-specific pathological processes.

Therapeutic Targeting of MCs in Neuroinflammation

The growing recognition of MCs as central regulators of neuroimmune interactions has stimulated interest in the development of therapeutic strategies aimed at modulating their activity. Given their involvement in BBB dysfunction, glial activation, oxidative stress, and cytokine signaling, targeting MCs represents a promising approach for attenuating neuroinflammation and limiting neuronal damage. Several pharmacological interventions have been investigated, ranging from classical MCs stabilizers and antihistamines to natural compounds and novel immunomodulatory agents. Although most evidence currently derives from experimental models and clinical translation remains limited, these approaches have provided valuable insights into the therapeutic potential of modulating MC-mediated pathways in neurological disorders. However, the therapeutic interpretation of these approaches requires caution. Many compounds proposed as mast cell-targeting agents are not selective for MCs and may exert their effects through additional cellular targets, including microglia, astrocytes, endothelial cells, and peripheral immune populations. Moreover, their translational potential depends on several factors, including BBB penetration, the relative contribution of central versus peripheral mast cell populations, disease stage, and the extent to which mast cell activation contributes to pathology in individual patients. Consequently, future clinical development will require the identification of reliable biomarkers capable of defining patient subgroups in which mast cell-directed interventions are most likely to provide therapeutic benefit. Therapeutic strategies focusing on mast cells (MCs) and neuroinflammation are summarized in Table 1.

Table 1.

Critical Overview of Therapeutic Strategies Targeting Mast Cell-Associated Pathways in Neuroinflammation

Therapeutic Class	Representative Agents	Main Target/Mechanism	Mast Cell Specificity	CNS/BBB Considerations	Evidence and Neurological Context	Main Neuroinflammatory Effects
Mast cell stabilizers	Cromolyn sodium	Inhibition of MC degranulation and mediator release	Limited; additional effects on other immune cells have been reported	Limited BBB penetration	Preclinical evidence in ischemic stroke and neurodegenerative settings; clinical evaluation of cromolyn-based approaches in AD	Reduced MC activation, histamine release, microglial activation, cytokine production, and neuroinflammation
	Ketotifen	H1 receptor antagonism and MC stabilization	Moderate; combines antihistaminic and MC-stabilizing actions	Able to cross the BBB	Mainly experimental evidence; clinical evidence in neurological disorders remains limited	Reduced cytokine production, oxidative stress, and inflammatory signaling
	Palmitoylethanolamide (PEA)	PPAR-α-associated modulation of MCs and glial cells	Low; pleiotropic neuroimmune modulator	Central and peripheral effects have been described experimentally	Preclinical neuroinflammatory models	Reduced NF-κB activation, cytokine release, glial reactivity, BBB dysfunction, and MC-associated markers
Antihistamines	H1 antagonists; H3 and H4 receptor-targeting agents	Modulation of histamine-dependent signaling	Variable; H3 effects are predominantly neuronal, whereas H4 is expressed on MCs and other immune cells	Depends on receptor subtype and individual compound	Preclinical evidence predominates; H3 antagonists have shown limited cognitive efficacy in AD clinical studies	Modulation of microglial activation, cytokine signaling, oxidative stress, and neuroimmune communication
Tyrosine kinase inhibitors	Imatinib, masitinib	Inhibition of KIT/SCF and other tyrosine kinase pathways	Limited; KIT is expressed by multiple hematopoietic and non-hematopoietic cell populations	Compound-dependent	Preclinical cerebral ischemia studies; masitinib evaluated clinically in AD and ALS	Reduced MC survival/activation, mediator release, BBB dysfunction, and inflammatory signaling
Natural compounds and flavonoids	Luteolin, quercetin	Modulation of intracellular signaling associated with MC activation and degranulation	Low; broad pleiotropic activity	CNS exposure and clinical relevance remain incompletely defined	Primarily in vitro and preclinical evidence	Reduced degranulation and release of histamine, cytokines, leukotrienes, prostaglandins, and tryptase
Biologics	Omalizumab, dupilumab	IgE neutralization or modulation of type 2 inflammatory signaling	Indirect; effects on MC activation arise through upstream immune pathways	Predominantly peripheral actions; neurological translation remains largely unexplored	Established efficacy in allergic/inflammatory diseases, but limited direct evidence in neurological disorders	Reduced MC sensitivity, degranulation, mediator release, and type 2 inflammatory signaling
Precision-medicine approaches	Molecular profiling and targeted therapies	Identification of disease- and patient-specific MC pathways	Potentially high, depending on the selected molecular target	Yet to be established	Emerging concept supported by genomics, transcriptomics, and single-cell approaches	Potential selection of patients with MC-driven neuroinflammatory phenotypes and individualized therapeutic targeting

MCs Stabilizers

Despite the increasing recognition of MCs as key orchestrators of neuroinflammation, relatively few therapeutic strategies have been specifically designed to modulate their activity. Most available approaches rely on compounds capable of preventing MCs degranulation or attenuating the release of inflammatory mediators, thereby limiting the downstream activation of glial cells and the propagation of neuroimmune signaling.

Cromolyn sodium, originally developed as an anti-allergic agent, is known as a “MC stabilizer”.⁹⁹ However, evidence suggests that cromolyn may exert additional effect.⁷ Cromolyn modulates ion transport through its actions on chlorine and calcium channels, suppresses cytokine secretion in microglia and reduces proinflammatory cytokine levels in mast cell-deficient mice, indicating MC-independent actions.⁷ Orally administered cromolyn is poorly absorbed from the gastrointestinal tract, with less than 1% of the administered dose reaching the systemic circulation, suggesting that some of its effects may originate predominantly from peripheral sites rather than from direct CNS exposure.^100,101 In an experimental model of ischemic stroke in aged mice, oral cromolyn reduced intestinal mast cell activation and circulating histamine and IL-6 levels, improved gut barrier integrity, decreased mast cell recruitment to the injured brain, and attenuated central neuroinflammation, supporting an indirect gut-periphery-brain mechanism of action.^102,103 Additional studies in neurodegenerative settings suggest that cromolyn may interfere with Aβ-associated inflammatory responses and attenuate microglial activation, supporting its potential role in disorders characterized by chronic neuroinflammation.¹⁰⁴

Importantly, translational efforts have led to clinical evaluation; for instance, the combination therapy ALZT-OP1 (which includes an inhalable cromolyn formulation with oral ibuprofen) was investigated in a randomized, double-blind, placebo-controlled Phase III clinical trial targeting patients with early Alzheimer’s disease, highlighting its potential utility during early disease stages where neuroinflammatory processes predominate.¹⁰⁵

In addition to cromolyn, other established mast-cell stabilizers, such as nedocromil, lodoxamide, and pemirolast, warrant critical evaluation regarding their potential applicability in neurological settings. These agents have not yet been directly evaluated or systematically investigated in neuroinflammatory conditions or neurodegenerative diseases; however, they could represent compelling candidates for future neuroinflammatory research based on specific mechanistic rationales. Beyond classical mast-cell stabilization, certain stabilizers exhibit key receptor-mediated actions; most notably, both lodoxamide and nedocromil act as potent agonists of GPR35,¹⁰⁶ a G-protein-coupled receptor expressed on microglial cells, monocytes/macrophages, and neural tissues. Given that emerging evidence points to GPR35 activation as a pathway capable of mitigating neuroinflammatory cascades, attenuating microglial hyperactivation, and modulating gut-brain immune signaling,¹⁰⁷ these off-target properties provide a strong theoretical framework for evaluating such molecules in CNS disorders. Pemirolast, and its novel deuterium-enriched derivatives, also represent promising candidates for neuroinflammatory research, for its ability to inhibit both antigen- and CP48/80-induced MC degranulation, blocking the upstream activation of resident brain MCs that triggers microglial hyperactivation. Furthermore, pemirolast could block neuroinflammatory cascades by suppressing intracellular Ca²⁺ uptake and release, inhibiting phosphodiesterase activity to elevate intracellular cAMP levels, and blocking arachidonic acid release and metabolism.¹⁰⁶

Ketotifen represents a particularly interesting example because its pharmacological profile combines H1 receptor antagonism with MC-stabilizing properties.¹⁰⁶ Beyond suppressing degranulation, ketotifen has been shown to modulate cytokine production and affect microglial activity, suggesting that its actions may extend beyond classical histaminergic pathways.¹⁰⁶ The ability of ketotifen to cross the BBB and influence central histaminergic signaling makes it an attractive candidate for drug repurposing, although clinical evidence in neuroinflammatory disorders remains scarce.¹⁰⁸ Experimental studies indicate that ketotifen may attenuate inflammatory responses and oxidative stress, but its efficacy in major neurological diseases still requires validation.¹⁰⁸

More recently, PEA has emerged as a pleiotropic endogenous lipid mediator capable of modulating both MCs and glial cells.¹⁰⁹ Rather than acting as a conventional stabilizer, PEA appears to restore neuroimmune homeostasis through mechanisms involving PPAR-α activation and the downregulation of inflammatory signaling pathways.¹¹⁰ Recent evidence has reinforced the concept of an MC-glia axis as a therapeutic target, with PEA reducing NF-κB activation, pro-inflammatory cytokine production, and glial reactivity.¹¹¹ Experimental studies have also shown attenuation of BBB dysfunction and reduced expression of MCs markers in the hippocampus, accompanied by improvements in behavioral and neuroinflammatory parameters.¹¹²

A major limitation of classical MC stabilizers, such as cromolyn sodium, is their poor lipophilicity and restricted BBB permeability, which largely limits their direct actions to peripheral MCs.¹¹³ Consequently, any neuroprotective effects observed in CNS models likely stem from the modulation of peripheral immune-brain signaling or the preservation of BBB integrity at the vascular interface.¹¹⁴ Moreover, many of these agents lack cell-type specificity, exerting off-target effects on microglial activation and endothelial reactivity.

Antihistamines

Given the prominent role of histamine as an early mediator released upon MCs activation, antihistamines have attracted interest as potential modulators of neuroinflammatory responses. Although traditionally used for allergic disorders, increasing evidence suggests that histamine receptor antagonists may exert broader immunomodulatory and neuroprotective effects by interfering with MC-mediated signaling, glial activation, and neuroimmune communication.¹¹⁵

Most studies have focused on H1 receptor antagonists, many of which possess anti-inflammatory properties that extend beyond the inhibition of histamine signaling. Compounds such as ketotifen, cetirizine, loratadine, and hydroxyzine have been shown to attenuate cytokine production, reduce vascular permeability, and modulate immune cell activity.¹¹⁶ In experimental settings, H1 receptor blockade has been associated with reduced microglial activation and attenuation of oxidative stress, suggesting that histaminergic pathways may contribute to the amplification of neuroinflammatory cascades.¹¹⁷ Beyond conventional H1 receptor antagonists, latrepirdine (Dimebon), originally developed as an antiallergic agent, has gained a great interest as a potential therapeutic agent for AD because of its proposed multimodal neuroprotective effects.¹¹⁸ Several studies have shown that latrepirdine is able to exert neuroprotective effects through several mechanisms, including reduction of oxidative stress and β-amyloid toxicity, reduction of glutamate neurotoxicity, activation of autophagy and inhibition of mitochondrial permeability pore function.¹¹⁸ However, its available clinical evidence in the context of AD is conflicting.^119–121

The complexity of histaminergic signaling, however, extends beyond H1 receptors. H2 receptors are also expressed in the CNS and on several immune cell populations, where histamine-mediated signaling can modulate neuronal and inflammatory responses.¹²² H2 receptor antagonists, including famotidine and cimetidine, are widely used clinically for gastric acid-related disorders;¹²³ however, their potential relevance to neuroinflammation remains much less established than that of H1-, H3-, or H4-directed approaches. Moreover, several commonly used H2 antagonists exhibit limited CNS penetration, and their effects on mast cell-associated neuroinflammation have not been clearly demonstrated. Thus, H2 receptor blockade should currently be regarded as a potential indirect modulatory strategy rather than an established mast cell-targeted therapy.

H3 receptors, predominantly expressed within the nervous system, regulate the release of histamine and other neurotransmitters, including dopamine, serotonin, and acetylcholine.¹²⁴ Their involvement in cognition, sleep-wake regulation, and synaptic plasticity has stimulated interest in H3-targeting agents for neurodegenerative and neuropsychiatric disorders.¹²⁵ Although their role in MC-mediated neuroinflammation remains incompletely understood, modulation of H3 signaling may indirectly influence inflammatory responses through neuronal pathways.¹²⁵ However, despite a strong preclinical rationale supporting H3 receptor modulation as a potential therapeutic strategy, clinical translation has been challenging. H3 receptor-targeting compounds such as ABT-288 and GSK239512 have failed to demonstrate meaningful cognitive benefits in patients with AD highlighting the gap between the promising preclinical evidence and clinical efficacy.^126–128

Particular attention has recently been directed toward H4 receptors, which are highly expressed on MCs and other immune cells.^129,130 H4 signaling participates in chemotaxis, cytokine release, and immune cell recruitment, placing this receptor at the crossroads between innate immunity and chronic inflammation. Experimental studies have shown that H4 receptor antagonism can suppress inflammatory responses and reduce tissue damage in several disease models, raising the possibility that targeting H4 signaling may provide a more selective approach than conventional antihistamines. Although no H4-targeting drugs have yet entered routine clinical practice, this receptor has emerged as a promising candidate for future neuroimmune therapies.

Rather than acting exclusively through the inhibition of histamine-dependent symptoms, antihistamines may therefore influence multiple components of the neuroinflammatory network. Their pleiotropic actions, together with their well-established clinical use and favorable tolerability, support further investigation into their potential repurposing for neurological disorders characterized by persistent MCs activation and dysregulated neuroimmune signaling.

Tyrosine Kinase Inhibitors

Tyrosine kinase inhibitors (TKIs) targeting the SCF/KIT signaling pathway have emerged as promising therapeutical approach for the modulation of mast cell activity in the context of neuroinflammatory disorders.⁹

KIT (CD117), a type III receptor tyrosine kinase and the receptor for stem cell factor (SCF), represents the principal regulator of mast cell development, survival, proliferation, and activation.¹³¹ However, KIT is also expressed by multiple other cell populations and plays important roles in the development and maintenance of hematopoietic and neuronal populations. Therefore, pharmacological inhibition of KIT signaling by TKIs is not equivalent to selective mast-cell inhibition and may produce broader cellular effects. Nevertheless, by interfering with KIT-dependent mast cell survival and recruitment, KIT-targeting approaches may reduce the release of pro-inflammatory mediators, including histamine, tryptase, cytokines, and chemokines, which can contribute to neuronal injury and neuroinflammation. Thus, modulation of the SCF/KIT axis may attenuate mast cell-associated inflammatory responses, although its potential effects on neuronal and vascular integrity within the CNS should be interpreted in the context of the broader, non-cell-specific actions of KIT inhibition.¹³¹

Several TKIs, such as imatinib and masitinib, have demonstrated promising effects in the context of neurological and neurodegenerative diseases.^9,132,133 In particular, masitinib, which inhibits KIT and other tyrosine kinases expressed by MCs, has shown promising results in patients with neurodegenerative disorders such as AD.¹³³ The study by Dubois et al¹³³ demonstrated that masitinib treatment regimens were associated with a slower rate of cognitive decline, reduced deterioration in activities of daily living, and clinical benefits in specific patient subgroups. Moroever, masitinib demonstrated to exert neuroprotective effects by inhibiting the upregulation of BBB permeability by MCs and suppressing neuroinflammation at the onset of AD.^9,133 Masitinib has also been investigated in amyotrophic lateral sclerosis (ALS), including in combination with riluzole, in the clinical trial NCT02588677, supporting broader clinical interest in its potential effects in neurodegenerative disorders.¹³⁴

Although the precise contribution of mast cell inhibition to the therapeutic effects of TKIs remains to be fully elucidated, growing evidence suggests that targeting mast cell-associated signaling pathways may represent a novel strategy for the treatment of neuroinflammatory and neurodegenerative diseases. TKIs offer superior CNS bioavailability compared to classical stabilizers.¹³⁵ However, because c-Kit is also expressed by other immune and progenitor cell populations, their therapeutic benefits cannot be attributed solely to MC inhibition. These broad-spectrum modulators may prove particularly advantageous in progressive or chronic disease stages, where sustained neuroinflammation involves complex crosstalk between MCs, microglia, and invading T cells.¹³⁶ However, further clinical studies are needed to determine the efficacy, safety, and long-term benefits of these agents in disorders characterized by mast cell-driven neuroinflammation.

Natural Compounds and Flavonoids

Natural compounds such as plant-derived flavonoids have gained increasing interest as potential modulators of mast cell activation due to their anti-inflammatory, antioxidant, and immunomodulatory properties.^137,138 Among these compounds, luteolin and quercetin have been extensively investigated for their ability to attenuate inflammatory responses by modulating mast cell activity.¹³⁷

Luteolin, a naturally occurring flavonoid present in several plants, exhibits modest anti-inflammatory effects.¹³⁹ Kempuraj et al¹⁴⁰ demonstrated that luteolin significantly inhibits myelin basic protein (MBP)-induced mast cell activation. Specifically, luteolin suppresses mast cell degranulation and reduces the production of inflammatory mediators, thereby attenuating mast cell-dependent activation of T cells. This suggests that luteolin exerts both direct inhibitory effects on MCs and indirect immunomodulatory effects on downstream immune effector cells.

Quercetin, another flavonoid widely present in fruits, vegetables, and tea, exhibits well-documented mast cell-stabilizing properties. Studies have shown that quercetin effectively inhibits mast cell activation triggered by cross-linking of the high-affinity IgE receptor (FcεRI), leading to a marked reduction in the release of key inflammatory mediators.¹⁴¹ In particular, quercetin suppresses the secretion of histamine, leukotrienes, and prostaglandin D2 (PGD2), thereby attenuating both early and late-phase allergic responses. Beyond lipid mediators, quercetin also modulates the production of pro-inflammatory cytokines and proteases. It has been demonstrated that quercetin reduces the release of IL-6, IL-8, and tumor necrosis factor-α (TNF-α), as well as the protease tryptase, highlighting its broad inhibitory effects on mast cell effector functions.¹⁴² These actions are mediated, at least in part, through the modulation of intracellular signaling pathways involved in calcium influx and kinase activation, ultimately leading to decreased degranulation and cytokine synthesis. Flavonoids, like luteolin and quercetin exhibit poor oral bioavailability and limited BBB permeability under physiological conditions.¹⁴³ Consequently, while peripheral mast cell stabilization can be achieved at lower doses, targeting meningeal or parenchymal MCs in CNS disorders may require higher doses, intranasal delivery, or advanced nano-formulations. Neither compound is strictly MCs-specific. Their pleiotropic actions extend to microglia, astrocytes, and peripheral lymphocytes, making it challenging to attribute observed therapeutic benefits exclusively to mast cell inhibition. Flavonoids demonstrate greater efficacy during early inflammatory stages or acute neuroinflammatory flares (by preventing degranulation and early mediator release) rather than reversing established chronic neurodegeneration or structural tissue damage.¹⁴⁴

Biologics and Emerging Therapies

Recent advances in the understanding of mast cell biology have promoted the development of biologic agents and targeted therapies aimed at specific molecular pathways involved in mast cell activation and inflammation.

One important strategy involves cytokine blockade. Several cytokines, including IL-4, IL-13, IL-33, and thymic stromal lymphopoietin (TSLP), play critical roles in promoting mast cell activation and sustaining type 2 immune responses. Monoclonal antibodies directed against these mediators or their receptors have shown clinical efficacy in allergic and inflammatory diseases in which mast cell activity is central to disease pathogenesis.

Among these, the anti-IgE monoclonal antibody omalizumab represents a well-established example of mast cell–targeted biologic therapy. By binding circulating free IgE, omalizumab prevents its interaction with the high-affinity IgE receptor (FcεRI) expressed on MCs and basophils. This results in a progressive downregulation of FcεRI expression and a consequent reduction in mast cell sensitivity to allergen-induced activation.¹⁴⁵ Through this mechanism, omalizumab decreases mast cell degranulation and mediator release, and has demonstrated clinical efficacy in asthma, chronic spontaneous urticaria, and selected mast cell–associated disorders.

In addition to anti-IgE therapy, biologics targeting IL-4/IL-13 signaling and IL-33 pathways are currently under investigation for their capacity to modulate mast cell-driven inflammation.¹⁴⁶

For instance, dupilumab, an anti-IL-4Rα monoclonal antibody, indirectly affects mast cell activity by suppressing the broader type 2 inflammatory milieu that supports their recruitment, survival, and activation. Its established clinical efficacy in asthma, atopic dermatitis, and related conditions further underscores the central contribution of mast cell-associated pathways in type 2 inflammatory diseases.¹⁴⁶ Its clinical efficacy in asthma, atopic dermatitis, and related diseases highlights the central role of mast cell–associated pathways in these conditions.

The emergence of precision medicine approaches has further expanded therapeutic opportunities. Advances in genomics, transcriptomics, and single-cell technologies have improved the understanding of mast cell heterogeneity and disease-specific molecular signatures. These approaches may allow the identification of patient subgroups with distinct pathogenic mechanisms and facilitate the selection of individualized therapies. While monoclonal antibodies provide potent targeted therapies, their clinical application requires careful consideration of their pharmacological limitations. Due to their large molecular size, biologics such as omalizumab and dupilumab exhibit virtually no BBB penetration under physiological conditions.¹⁴⁷

Future treatment strategies will likely integrate molecular profiling, targeted biologics, and personalized therapeutic interventions aimed at specific mast cell populations or signaling pathways. Such precision medicine approaches hold considerable promise for improving clinical outcomes in allergic, inflammatory, neuroimmune, and mast cell-associated diseases.

Figure 4 summarizes the main therapeutic strategies targeting MCs and their signaling pathways to attenuate neuroinflammation and limit neuronal damage discussed in this paragraph.

Figure 4.

Pharmacological Targeting of MCs in Neuroinflammation: Current and Emerging Therapeutic Strategies. Overview of pharmacological approaches aimed at modulating MCs activity, including mast cell stabilizers, antihistamines, natural compounds, tyrosine kinase inhibitors, biologic agents, and emerging targeted strategies. These interventions may attenuate MC-mediated neuroinflammation by reducing mediator release, glial activation, oxidative stress, BBB dysfunction, and neuronal damage.

Conclusions and Future Perspectives

Over the last decade, significant advances have reshaped our understanding of the role of MCs in neuroinflammation. Traditionally viewed as effector cells primarily involved in allergic responses, MCs are now recognized as active participants in neuroimmune regulation, capable of influencing BBB integrity, glial activation, oxidative stress, inflammasome signaling, and peripheral-central immune communication. Their strategic localization and broad repertoire of mediators position them as important modulators of both physiological and pathological processes within the CNS.

Nevertheless, several challenges still limit the translation of current knowledge into effective therapeutic strategies. One major obstacle arises from the remarkable heterogeneity of MCs populations, which exhibit tissue-specific phenotypes and functional diversity that are not yet fully understood. The lack of reliable and highly specific markers further complicates the identification and characterization of MCs subsets, making it difficult to distinguish their context-dependent roles in different neurological disorders.

Another important limitation concerns the interpretation of preclinical data. A substantial proportion of the foundational literature investigating mast cell functions, including their involvement in neuroinflammatory processes, was generated using KIT-dependent mast cell-deficient models, particularly KitW/Wv and KitW-sh/W-sh mice. Although these models have provided important mechanistic insights, KIT signaling is not restricted to MCs, and KIT mutations can affect several hematopoietic and non-hematopoietic cell populations. Consequently, phenotypes observed in these animals cannot always be attributed exclusively to mast cell deficiency. More recently, the field has increasingly adopted KIT-independent models, including Cpa3- and Mcpt5-based approaches, which allow a more selective assessment of mast cell functions. Nevertheless, these newer models also present specific limitations, including incomplete depletion of particular mast cell subsets or effects on other immune cell populations. Therefore, both historical and contemporary findings obtained using mast cell-deficient models should be interpreted in light of the specific characteristics and limitations of each experimental system.

The increasing recognition of patient-specific molecular and immunological profiles is also paving the way toward personalized neuroimmunology. Future therapeutic strategies will likely require integrated approaches aimed at modulating multiple components of the neuroinflammatory network rather than targeting isolated pathways. In this context, combining MC-directed therapies with interventions acting on microglia, inflammasomes, or BBB dysfunction may represent a promising avenue for improving clinical outcomes.

Rather than passive bystanders, MCs should now be considered dynamic regulators of neuroimmune communication and key nodes within the complex network underlying neuroinflammation. Although their therapeutic potential remains incompletely defined, the growing body of experimental and clinical evidence supports the view that targeting MC-mediated pathways may offer new opportunities for the treatment of neurological disorders. Continued advances in systems biology, single-cell technologies, and precision medicine are expected to further clarify the role of MCs and accelerate the development of more effective and individualized therapeutic strategies.

Funding Statement

This research received no external funding.

Data Sharing Statement

All data of this study are included in this published article.

Author Contributions

A.A. Writing-original draft, Conceptualization

S.A.S. Writing-original draft, Investigation

R.B. Methodology, Writing-review and editing

L.C. Methodology, Writing-review and editing

E.E. Supervision, Conceptualization, Writing-review and 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

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.