IL-4 Signal Regulates IL-9-producing Mucosal Mast Cell Differentiation And Function During The Development of Experimental Food Allergy

Abstract

Abstract The prevalence of food allergy is increasing significantly in developed nations. Accumulating evidences suggest a pivotal role of intestinal mast cells (MCs), TH2 cytokines, and IgE in the pathophysiology of food allergy. We have recently identified the novel IL-9 producing mucosal mast cells (MMC9s), which can produce high levels of IL-9, IL-13, and mast cells mediators. Mice deficient of IL-4 signals fail to develop MMC9s and become resistant to IgE-mediated food allergy. However, it remains unclear whether IL-4 can directly regulate the development and function of MMC9s. In a skin sensitization induced food allergy model, Il4RaF709 mice which have gain-of-function mutations in IL-4Ra were found to produce much higher levels of ovalbumin (OVA) specific IgE and mast cell protease-1 in blood and became more susceptible to experimental food allergy. While the occurrence of MMC9s and type-2 innate lymphoid cells (ILC2s) were comparable between wild type (WT) and Il4RaF709 mice, repeated OVA ingestions induced significant increase of CD4+TH2 cell occurrence and MC numbers in the small intestine of Il4RaF709 mice than those in WT mice. Furthermore, IL-4 treatments induced bone marrow derived mast cells (BMMCs) from Il4RaF709 mice to produce much more IL-13 and TNF-α than those by WT BMMCs. These results suggest that IL-4 signal provided by CD4+TH2 cells may directly potentiate TH2 effector function of MMC9s and promote the differentiation of MMC9s into intestinal mature MCs, resulting in the increased intestinal hypersensitivity to ingested food allergens. Detailed mechanistic studies of IL-4 signaling in MMC9 development and function may provide therapeutic insights into the preventions and treatments of food allergy.