Roles of Mast Cells in Cutaneous Diseases

Abstract

Mast cells are present in all vascularized tissues of the body. They are especially abundant in tissues that are in frequent contact with the surrounding environment and act as potential sources of inflammatory and/or regulatory mediators during development of various infections and diseases. Mature mast cells' cytoplasm contains numerous granules that store a variety of chemical mediators, cytokines, proteoglycans, and proteases. Mast cells are activated via various cell surface receptors, including FcϵRI, toll-like receptors (TLR), Mas-related G-protein-coupled receptor X2 (MRGPRX2), and cytokine receptors. IgE-mediated mast cell activation results in release of histamine and other contents of their granules into the extracellular environment, contributing to host defense against pathogens. TLRs, play a crucial role in host defense against various types of pathogens by recognizing pathogen-associated molecular patterns. On the other hand, excessive/inappropriate mast cell activation can cause various disorders. Here, we review the published literature regarding the known and potential inflammatory and regulatory roles of mast cells in cutaneous inflammation, including atopic dermatitis, psoriasis, and contact dermatitis GVHD, as well as in host defense against pathogens.

Keywords: allergy; autoimmunity; infection; rejection; skin disease.

Figure 1

Mast cells in skin inflammation during infection. Mast cells (MCs) are important for host defense against various pathogens. On the other hand, inappropriate MC activation during infection results in aggravation of such skin diseases as AD and acne vulgaris. Blue arrows: appropriate MC activation; red arrows: excessive MC activation.

Figure 2

Mast cells in acute contact hypersensitivity. Mast cell (MC)-derived TNF enhances skin dendritic cell (DC) migration to draining LNs, leading to induction of hapten-specific Th-cell expansion in the sensitization phase of contact hypersensitivity (CHS). MC-derived IL-25 induces IL-1β production by dermal DCs, followed by promotion of IL-17 production by Th17 cells in the elicitation phase of CHS. Histamine has dual roles, i.e., inflammatory and anti-inflammatory, in the elicitation phase of CHS. Haptens stimulate keratinocytes (KCs) to produce PAMP9-20, a ligand for Mrgprb2. PAMP9-20 induces itch during CHS.

Figure 3

Mast cells in chronic contact hypersensitivity. In one chronic contact hypersensitivity (CHS) setting, crosslinked hapten/hapten-specific IgG complexes stimulate skin mast cells (MCs) to produce IL-10, which leads to suppression of the inflammation. In another chronic CHS setting, crosslinking of hapten/hapten-specific IgE/FcϵR1 results in production of IL-2 by splenic MCs, which leads to expansion of Tregs in the spleen. The Tregs migrate from the spleen to local skin lesions, where they suppress the inflammation.

Figure 4

Mast cells in psoriasis. Mast cells (MCs) produce TNF in response to imiquimod via TLR7, and TNF then promotes dendritic cell (DC) migration from the skin to draining LNs. The migrated DCs induce CD8⁺ T-cell expansion in the peripheral blood.

Figure 5

Mast cells in collagen synthesis (wound healing and fibrosis). When the skin is wounded, mast cells (MCs) degranulate and release various mediators that enhance vascular permeability and recruitment of inflammatory cells to injured sites in the early stage (inflammatory phase). In addition, MC-derived histamine, tryptase and chymase induce fibroblasts to produce collagen, which is involved in tissue remodeling and development of scleroderma in the late stage (proliferative phase).

Figure 6

Mast cells in skin allografts. Regulatory T-cell (Treg-)derived IL-9 induces mast cell (MC) accumulation and activation in skin allografts. The Tregs and MCs then suppress CD8+ T-cell-mediated allograft rejection.

Figure 7

Summary of roles of mast cells in cutaneous diseases. Mast cells are potential sources of inflammatory and/or regulatory mediators during development of various cutaneous infections and diseases.