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Review
, 122, 211-52

Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing

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Review

Development of Mast Cells and Importance of Their Tryptase and Chymase Serine Proteases in Inflammation and Wound Healing

Jeffrey Douaiher et al. Adv Immunol.

Abstract

Mast cells (MCs) are active participants in blood coagulation and innate and acquired immunity. This review focuses on the development of mouse and human MCs, as well as the involvement of their granule serine proteases in inflammation and the connective tissue remodeling that occurs during the different phases of the healing process of wounded skin and other organs. The accumulated data suggest that MCs, their tryptases, and their chymases play important roles in tissue repair. While MCs initially promote healing, they can be detrimental if they are chronically stimulated or if too many MCs become activated at the same time. The possibility that MCs and their granule serine proteases contribute to the formation of keloid and hypertrophic scars makes them potential targets for therapeutic intervention in the repair of damaged skin.

Keywords: Chymase; Connective tissue remodeling; Inflammation; Mast cell; Matrix metalloproteinase; Serine protease; Tryptase; Wound healing.

Figures

Figure 6.1
Figure 6.1
Development of cutaneous MCs from their hematopoietic progenitors. The bone marrow (A) constitutively releases MC-committed progenitors (MCp) into the blood. These circulating, nongranulated CD34+ progenitors enter the skin and other organs when they encounter the appropriate combination of chemokines (e.g., Ccl5) and other recruitment factors (B). The retention of these progenitors in tissues also is highly dependent on Kitlg (▼), Kit, Cadm1, and varied integrins (I). Once in the skin, the progenitors undergo their final stages of differentiation and maturation. This includes their expression and granule accumulation of different combinations of protease–SGPG complexes. The phenotype of an MC at any stage of its life span is highly dependent on the factors the mature cell and its progenitor encounter in the tissue microenvironments. A mature MC can even reversibility alter what genes and proteins it expresses. Although fibroblast-derived Kitlg and IL-33 are essential in the development of cutaneous MCs, other cytokines (e.g., TGF-β and IL-9) play important roles in determining what families of mediators are expressed.
Figure 6.2
Figure 6.2
Exocytosed mediators from activated MCs. The MCs that reside in the skin and other connective tissues contain numerous receptors on their plasma membranes that they use in innate (e.g., complement and TLRs) and acquired (e.g., FcεRI and FcγRIII) immunity. MCs also can recognize and respond to numerous endogenous factors like ATP that are often increased in wounded skin, as well as epitopes recognized by naturally occurring IgM autoantibodies. In the early phase, activated MCs rapidly exocytose the contents of their secretory granules and increase their expression of varied lipid mediators. In the late phase, the activated cell markedly increases the expression of numerous cytokines and chemokines. MCs also have inhibitory receptors that dampen cellular activation.
Figure 6.3
Figure 6.3
Histochemistry of nonactivated and activated cutaneous MCs. Mature MCs are recognized in the skin and other tissues histochemically by the ability of their SGPGs to bind to toluidine blue and other cationic dyes. Cutaneous MCs tend to reside near blood vessels (A), hair follicles (B), and nerves (data not shown). When activated (C), cutaneous MCs quickly exocytose the content of their secretory granules which consist primarily of histamine and varied protease–SGPG complexes. Most of the cell’s positively charged granule proteases (D) (e.g., mMCP-5 (5), Cpa3 (A), mMCP-4 (4), and mMCP-6 (6)) are ionically bound so tightly to the negatively charged glycosaminoglycans (GAGs) of SGPGs that the exocytosed macromolecular complexes remain intact for hours in the ECM. An exception is mMCP-7 (7), due to its less positively charged SGPG-binding domain. The large size of these protease–SGPG complexes minimize their diffusion and ability to enter the circulation. Instead, most of them are eventually endocytosed by other cell types in the inflammatory site where they are destroyed in primary lysosomes. The depicted images in panels (A)–(C) were from surgically wounded mouse skin.
Figure 6.4
Figure 6.4
Roles of MCs in different stages of wound repair. MCs and their mediators play important roles in hemostasis and in the inflammation, proliferation, and remodeling phases of wound healing.

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