[Academic Presentation] The Role of Mast Cells in Dermatological Diseases

Article reprinted from: Chinese Medical Abstracts – Dermatology, Issue 2, 2017.

Authors: Liu Dan, Gao Jun, Ren Wanming

As the largest organ of the human body, the skin serves as a boundary between the internal and external environments and functions as an essential physical barrier. It is also a key immune organ, interacting with other components of the immune system to form a complex network that collectively maintains homeostasis in both the cutaneous microenvironment and the systemic milieu. Mast cells are among the principal immune cells of the skin, widely distributed throughout connective tissues; they are particularly abundant around capillaries and lymphatics, as well as in the perineural spaces of submucosal connective tissue in the skin, respiratory tract, gastrointestinal tract, and urogenital tract. This distribution pattern underscores the critical role of mast cells as a first line of defense against pathogen invasion. Upon activation by diverse physical, chemical, and biological stimuli, mast cells release a variety of bioactive mediators through degranulation, thereby eliciting corresponding physiological and pathological responses. The specific bioactive factors, lipid mediators, proteases, and other molecules released during different dermatological conditions vary, and their mechanisms of action are not identical. This review summarizes the roles of mast cells in various skin diseases.

1 Mastocytosis

Mastocytosis is a clonal disorder characterized primarily by the accumulation and proliferation of mast cells in one or more organs, encompassing cutaneous mastocytosis and systemic mastocytosis. Its pathogenesis is associated with autophosphorylation of the c‑KIT protein resulting from point mutations in the c‑KIT gene. Cutaneous mastocytosis is the most common form of mastocytosis, frequently observed in children, and clinically presents as localized epidermal pigmentation on the trunk and extremities; it may also manifest as friction‑induced urticaria (Darier’s sign), with vesicles or bullous lesions appearing when the Darier’s sign exacerbates. Systemic mastocytosis, on the other hand, predominantly affects adults and, in addition to typical skin lesions, may be accompanied by systemic symptoms such as nausea, vomiting, abdominal pain, diarrhea, generalized anaphylaxis, and osteoporosis. Whether cutaneous or systemic, these manifestations are largely attributable to mediators secreted and released by abnormally proliferating mast cells.

2 The Role of Mast Cells in Urticaria

Urticaria is a localized edematous reaction resulting from the reactive dilation and increased permeability of small blood vessels in the skin and mucous membranes. Mast cells are the principal effector cells in urticarial reactions and also serve as the initiating effector cells in type I hypersensitivity reactions. Its pathogenesis can be classified into hypersensitive and non‑hypersensitive mechanisms: non‑hypersensitive reactions typically arise when certain foods, drugs, or physical and mechanical stimuli directly trigger mast cells to release histamine, thereby precipitating urticaria; hypersensitive reactions are predominantly type I, characterized by the following sequence: upon entry of an allergen, it encounters macrophages, which present antigenic information and stimulate B lymphocytes to produce antigen‑specific IgE antibodies. These antibodies bind with high‑affinity FcεRI receptors on the surface of mast cells, rendering the organism sensitized. When the same or a similar allergen re‑enters the body, the two adjacent high‑affinity IgE receptors on the sensitized mast cell become cross‑linked by the antigen, activating intracellular signaling pathways that prompt rapid degranulation and the release of a cascade of bioactive mediators—including histamine, leukotrienes, tryptase, prostaglandins, and interleukins—which in turn activate downstream secondary effector cells. This leads to capillary dilation, increased vascular permeability, enhanced glandular secretion, and other pathological changes, manifesting as local or systemic allergic symptoms affecting the skin, mucous membranes, respiratory tract, and gastrointestinal tract.

3 The Role of Mast Cells in Atopic Dermatitis

Atopic dermatitis is a chronic inflammatory skin disease associated with a genetically determined allergic diathesis, characterized by pruritus, polymorphic skin lesions, and a tendency to exudation, often accompanied by asthma and allergic rhinitis. Mast cells play a central role in the pathogenesis of hypersensitivity‑mediated inflammatory diseases; under inflammatory conditions, they upregulate FcεRI, enhancing their binding to IgE antibodies and facilitating activation upon antigen encounter, as well as the secretion of cytokines and inflammatory mediators. In the early phase of allergen challenge, the primary response is mediated chiefly by mast cells and other innate effector cells; by 4 hours later, the late‑phase reaction reflects the actions of secondary effector cells, such as eosinophils and neutrophils. Various inflammatory mediators and cytokines released by mast cells modulate immune responses by influencing antigen‑specific lymphocyte activation. IL‑4 secreted by mast cells promotes the differentiation of Th0 cells into Th2 cells; in turn, IL‑4 and IL‑5 produced by Th2 cells stimulate IgE synthesis and eosinophil activation. Consequently, approximately 80% of patients with atopic dermatitis exhibit elevated serum IgE levels, and Th2 cells are markedly increased in lesional skin. Mast cells can also recruit Th1, Th2, and CD8+ T cells—cells expressing LTB4 receptors—to sites of inflammation by releasing leukotriene B4 (LTB4). Moreover, TNF‑α released by mast cells upregulates the expression of endothelial adhesion molecules, including vascular cell adhesion molecule‑1 (VCAM‑1) and E‑selectin, thereby facilitating the entry of circulating lymphocytes into inflamed tissues. Trypsin and histamine activate neutrophils, contributing to host immune responses, while lipid mediators recruit T lymphocytes and induce the activation and proliferation of antigen‑specific CD8+ T cells, which then secrete IL‑2, IFN‑γ, and macrophage inflammatory proteins. Additionally, mast cells accelerate dendritic cell maturation and enhance their function, and by releasing tumor necrosis factor, they further promote the migration of dendritic cells to inflammatory sites.

4 The Role of Mast Cells in Psoriasis

Psoriasis is a common chronic inflammatory skin disease resulting from the combined effects of genetic, environmental, and immune factors. Clinically, it manifests as erythematous, scaly plaques of varying sizes. Histopathologically, it is characterized by epidermal hyperproliferation and impaired maturation, along with inflammatory cell infiltration. Psoriasis is closely linked to a complex cascade of events initiated by inflammatory mediators. Cytokines play a pivotal role in the pathophysiology of psoriasis. IL‑33, the newest member of the IL‑1 family of proinflammatory cytokines, can induce mature mast cells derived from human bone marrow stem cells to release IL‑8, which in turn recruits neutrophils. The IL‑33 released by mast cells further promotes lymphocyte infiltration, keratinocyte proliferation, and endothelial cell hyperplasia. Studies have shown that sphingolipid metabolites, such as sphingosine‑1‑phosphate (S1P), are key mediators of mast cell activation in allergic reactions; IL‑33 can potentiate S1P‑induced mast cell degranulation and the release of vascular endothelial growth factor (VEGF). VEGF, an angiogenic factor implicated in numerous inflammatory conditions, drives endothelial cell proliferation and increases vascular permeability, thereby playing a critical role in the pathogenesis of psoriasis. As psoriasis progresses, mast cells become increasingly activated, and the expression of corticotropin‑releasing hormone receptor‑1 (CRHR‑1) rises markedly; activated mast cells, through CRHR‑1 signaling, further enhance vascular permeability. Research indicates that in psoriatic lesions, cytokines such as IL‑17 and IL‑22—secreted by mast cells—are significantly elevated. These cytokines jointly suppress keratinocyte differentiation while promoting keratinocyte proliferation and migration toward the upper epidermis, leading to features characteristic of psoriatic lesions, including parakeratosis, hyperkeratosis, and elongated epidermal ridges.

5 The role of mast cells in keloids

Keloids are fibrous neoplasms that develop secondary to skin injuries such as incisions or lacerations. They represent a chronic inflammatory condition, histologically characterized by an excessive accumulation of extracellular matrix, localized infiltration of inflammatory cells—including mast cells—and a substantial deposition of cytokines. At present, the precise role of mast cells in the pathogenesis of keloids remains unclear; however, numerous studies have demonstrated that mast cells play a critical role in the proliferation and growth of effector cells—fibroblasts—in keloid tissue. The bioactive mediators and cytokines synthesized and secreted by mast cells, such as trypsin, chymase, inflammatory mediators and cytokines like tumor necrosis factor‑α (TNF‑α), leukotrienes, and prostaglandin E2 (PGE2), stimulate fibroblast proliferation and excessive extracellular matrix deposition, thereby promoting tissue fibrosis. In keloids, both the number of mast cells and the activities of mast cell‑derived chymase and tryptase are markedly elevated compared with normal skin. Chymase and tryptase exert dual effects on collagen synthesis and tissue remodeling: tryptase can both promote fibroblast proliferation and activate collagenases, facilitating the conversion of procollagen into fibrillar collagen, while also degrading fibrinogen and various extracellular matrix proteins by activating matrix metalloproteinases and collagenases. Similarly, chymase can either enhance the degradation of collagen and other extracellular matrix proteins through activation of metalloproteinases, or stimulate the release of transforming growth factor‑β, thereby promoting fibroblast proliferation. Furthermore, chymase can catalyze the conversion of angiotensin I to angiotensin II, which in turn promotes the reorganization of fibrous tissue.

6 The Role of Mast Cells in Autoimmune Bullous Diseases

Bullous skin diseases are a group of dermatoses that affect the skin and mucous membranes, characterized by vesicles and bullae as their primary lesions. Based on their pathogenesis, they can be classified into “autoimmune bullous diseases” and “non‑autoimmune bullous diseases.” Bullous pemphigoid is the most common autoimmune bullous skin disease; clinically, it presents with tense, difficult-to‑rupture bullae, erosions, crusts, macules, and delayed, intense pruritus. The key pathological features include subepidermal blisters, IgG and C3 deposition along the basement membrane zone, and the presence in serum of antibodies directed against basement membrane components—specifically the hemidesmosomal antigens BP230 and BP180. As an autoimmune disorder, the pathogenesis of pemphigus involves both cellular and humoral immunity, with T‑helper cells serving as critical mediators in both arms. Mast cells are increased in the lesional skin of bullous pemphigoid, and the concentrations of mast cell‑derived mediators and proteases are elevated in affected patients. Mast cells can present antigens to T cells or secrete cytokines that modulate T‑cell function and activation; for example, IL‑4 secreted by mast cells can drive Th0 cells to differentiate into Th2 cells. The cytokines released by Th2 cells (IL‑4, IL‑5, IL‑6, IL‑10, and IL‑13) promote B‑cell proliferation, differentiation, and antibody production, thereby participating in the humoral immune response.

7 The Role of Mast Cells in Cutaneous Candidiasis

Candida is one of the most common opportunistic pathogens in humans. Disruption of the skin–mucosal barrier due to various factors, endocrine dysregulation, and antibiotic overuse—leading to microbial imbalance—can predispose individuals, particularly those with immunosuppression, to severe fungal infections caused by these conditional pathogens. Candida albicans is the principal pathogen, colonizing the skin and mucosal surfaces in a commensal state. Mast cells in the skin are among the first immune cells to encounter C. albicans directly; however, the nature of their interaction remains poorly understood. At different stages of the immune response—early, mid, and late—mast cells degranulate and release distinct cytokines that contribute to antifungal immunity. In the initial phase, C. albicans can rapidly induce mast cell degranulation; the specialized cytokines released form an extracellular matrix that transiently inhibits C. albicans’ viability and diminishes its ability to establish colonization on the skin. Meanwhile, internalized C. albicans can proliferate within mast cells, ultimately leading to mast cell death. Furthermore, infected mast cells secrete cytokines that recruit neutrophils. In the later stages of the response, mast cells also release anti‑inflammatory cytokines to modulate the immune reaction. These interactions between mast cells and fungi demonstrate that mast cells can regulate the host’s antifungal immune response by producing and releasing specific cytokines.

8 Conclusion

Mast cells release a variety of bioactive mediators through degranulation upon stimulation. Given the diverse array of bioactive substances they produce in the pathogenesis of various skin diseases, as well as the multiplicity of their interactions with pathogens and other immune cells, the precise mechanisms by which mast cells contribute to cutaneous pathophysiology remain unclear. In-depth investigation of mast cell functions in skin disorders will help elucidate the underlying pathogenic processes of certain dermatoses and pave the way for novel therapeutic strategies and options.

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