INSIGHTS INTO THE REGULATION OF MAST CELL FUNCTION IN TYPE 2 INFLAMMATION.

Abstract

Type 2 inflammation (T2I) underlies the pathogenesis of asthma, chronic rhinosinusitis with nasal polyps, and eosinophilic esophagitis. Mast cells (MCs) are tissue resident hematopoietic effector cells thought to play major roles in T2I. Two subtypes of human MCs are recognized based on immunohistochemical differences. MCs expressing tryptase but not chymase (MC_T) reside within mucosal epithelial surfaces, and MCs expressing tryptase, chymase, and cathepsin G (MC_TC) reside in submucosal, perivascular and intraneural locations. During T2I, MCs (particularly MC_T) increase markedly by unclear mechanisms. Single cell genomic studies reveal that traditional histochemical categorization vastly underestimates the extent of MC functional heterogeneity. MC_T and MC_TC likely reflect endpoints of a developmental continuum, emerging from a transitional stage of development in which MCs expand through in situ proliferation. This mechanism, likely driven by interleukin 4 and other cytokines, is unique among granulocytes and carries substantial implications for pathogenesis and therapy of T2I-associated diseases.