Introduction
Innate Immune Cells in Asthma (Recruitment and Function)
Mast Cell Progenitors from Bone Marrow to Airways: Production and Homing
Role of MC Mediators in Allergic Asthma
Preformed mediators | ||
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Chymase | Activates MMP-9, consequently degradation of the ECM and basement membrane (BM), migration of endothelial cells into the interstitial space, and endothelial cell proliferation and differentiation into mature blood vessels occur. It generates mature forms of IL-33 by acting on full-length IL-331–270 to activate ILC2s and eosinophils in vivo. | [40] [41] |
Histamine | Upon MC degranulation, histamine causes immediate bronchoconstriction via H1 receptors. The levels in the BAL fluid directly correlate with the severity of asthma. | [42] |
Tryptase | Tryptase induces AHR by activating ASM expressed PAR-2 and has been implicated in bronchoconstriction through release of neurokinins from afferent neurons in the airways. It promotes tissue remodeling and fibrosis. Upon releasing from MCs, it induces HASM to release TGFβ1 which promotes the expression of α-smooth muscle actin (α-SMA) by HASMC and induces the contractility. | [43] [44] [45] |
De novo synthesized mediators | ||
PGD2 | PGD2 is a chemoattractant for HASM when acts on CRTH2/DP2 receptor (expressed by eosinophils, basophils, and epithelial cells in addition of HASM) and may promote ASM migration toward the subepithelial BM. Additionally, when released from MCs, PGD2 acts as bronchoconstrictor. PGD2/DP2 interaction facilitates the trafficking of inflammatory cells into cite of inflammation by increasing smooth muscle relaxation, vasodilation, vascular permeability, and production of CCL22 by epithelial cells. | [46] [47] [47] |
LTC4 | Acting through Cys-LT1, LTC4 promotes variety of physiopathologic reactions in airways mainly acute bronchoconstriction, eosinophil chemotaxis and activation, mucus hypersecretion, hyperplasia, and contraction of ASM. | |
LTE4 | LTE4 induces airflow obstruction and MC activation when acts on CysLT1 receptor. | [50] |
PAF | PAF an important pro-inflammatory mediator causes bronchial hyperactivity, increased vascular permeability, and accumulation of inflammatory cells. | [51] |
Released cytokines | ||
IL-4 | IL-4 as a pleiotropic cytokine acting via the IL-4R on majority of lung cells is associated with remodeling of epithelium and lamina propria. It also supports smooth muscle cell contractility. IL-4 supports the expression of FcεRI on MCs and basophils. In addition to MCs, other immune cells including Th2 cells, eosinophils, basophils, and ILC-2 are capable of producing and releasing IL-4. | [52] [52] |
IL-13 | IL-13 expression promotes inflammatory cell release, production of eotaxin and FeNO, mucus hypersecretion, and supports subepithelial fibrosis. | |
TSLP | MCs express the TSLP receptor, and TSLP/TSLP receptor interaction results in expression of Th2 cytokines. MCs are known to produce high levels of TSLP, upon IgE-mediated activation. | [56] |
TGFβ1 | TGFβ1 along with bFGF and PAF is a key mediator in fibrotic pathways. These mediators are associated with differentiation of the myofibroblasts which act as the key cell type involved in pulmonary fibrosis. TGFβ is well known for its profibrotic mediating properties in the lung which supports collagen synthesis. | [57] [9] |
IL-33 | IL-33 enhances IgE/Ag-, monomeric IgE-, C5a-, SCF-, and NGF-mediated cytokine production in human MCs, and HMC-1. | [58] |
VEGF | MC and eosinophil-derived VEGF act as angiogenic factor in the asthmatic submucosa. | [59] |
bFGF-2 | Acts as a profibrogenic cytokine during airway remodeling. | [60] |