Figure 1. Schematic, highly simplified representation of the potential roles of MCs in airway chronic allergic inflammation and remodeling.

Individuals not yet sensitized to environmental allergens do not have specific IgE to such allergens, and few MCs are present within the epithelium (left panel). During allergic sensitization, environmental antigens (Ag) are captured by APCs in the airway lumen or in the epithelium of the airway mucosa, and Ag-activated APCs mature and migrate to regional lymph nodes, where priming of T cells occurs (not shown). The presence of IL-4 or IL-13, which may be derived from a variety of potential cellular sources, induces T cells to become T_H2 cells (right panel). In some cases, allergens also can reach APCs in the submucosa through damaged epithelium. Cytokines induced by epithelial damage (such as IL-33 and TSLP) can activate ILC2 cells, which secrete type 2 cytokines, such as IL-4 and IL-13. The Th2 environment promotes heavy-chain class switching from IgM or IgG to IgE for Ag-specific IgE production in B cells. IgE binds to FcεRI on MCs (and basophils) and sensitizes these cells to respond to subsequent Ag exposures. Ag-induced aggregation of IgE-bound FcεRI causes the prompt release of pre-stored MC mediators, including histamine and TNF, which can promote bronchoconstriction and, more slowly, fibroblast proliferation. FcεRI activation also induces the production and the release of de novo synthesized compounds, such as leukotrienes, prostaglandins, and pro-inflammatory cytokines (e.g., IL-5, IL-6, IL-8, IL-13, and TNF) and chemokines (not shown), that contribute to the development of local inflammation.

Both soluble factors, such as IFN-γ, TSLP, IL-33, S1P, LPS (through PRRs) and cells present at the site, such as T_H cells and various T_reg cells (not shown), which can interact with OX40L on MCs, modulating IgE-dependent MC activation, or B cells, which can interact with CD40L on MCs, which may enhance B cell IgE production. At least one MC-secreted product, MCPT4 (not shown), can negatively regulate the inflammatory environment, in part through the degradation of IL-33.

Repetitive exposure to specific Ag favors persistent inflammation (with large numbers of eosinophils, and with MCs appearing within the epithelium), goblet cell hyperplasia and increased mucus secretion, smooth muscle cell proliferation, increased vascular permeability (and increased numbers of blood vessels) and airway edema, thickening and remodeling. In some asthma subtypes, genetic or environmental factors, including pathogen-derived products, tissue damage, airway pollutants, and oxidative stress, may confer strong T_H1 and/or T_H17 signatures associated with large numbers of neutrophils at the site of inflammation. Studies in MC–knockin mice have indicated that some actions of MCs, such as increasing the number of epithelial goblet cells, can occur in a model of chronic allergic inflammation by MC–dependent mechanisms that do not require MC signaling through the FcεRIγ chain, whereas MCs must express both the FcεRIγ chain and the IFN-γ receptor 1 (IFN-γR1) to mediate substantial increases in lung eosinophils and neutrophils. Note: down-regulatory mechanisms that can be engaged in this setting, such as co-engagement by multivalent Ag of both FcεRI and FcγRIIb, or effects of regulatory T cell populations, are not shown.

AhR, Aryl hydrocarbon receptor; Baso, basophils; Eos, eosinophils; FcεRI, high affinity receptor for IgE; ILC2, innate lymphoid cells type 2; Neu, neutrophils; PRR, pattern recognition receptor; TH, T helper; TSLP, thymic stromal lymphopoietin.