Dissecting distinctive roles of GAB scaffolding proteins in allergic inflammation in vivo

Abstract

Scaffolding proteins Gab1 and Gab2 are ubiquitously expressed and belong to the GAB family (GABs), which integrates multiple signal events. This protein family has recently attracted interest as genetic variants of human GAB1 are considered a risk factor for asthma; however, GAB functions in lungs remain unclear. Previous studies have suggested that GABs have functional redundancy, due to their highly homology. We show here that both Gab1 and Gab2 are key factors in allergic inflammation, but have different functions. Firstly, we observed increased levels of both in lungs from ovalbumin (OVA)‐challenged mice. Further analysis indicated that Gab1 is mainly elevated in dendritic cells (DCs), while Gab2 is found in airway epithelial cells. Gab2‐knockout mice exhibited a marked reduction in mucus production and attenuated Goblet cell hyperplasia (GCH). We further recently characterized a unique role for Gab1 in DCs, which are essential for initiating and maintaining adaptive Th2 cell responses to allergens. Using a Cre‐loxP system, we generated myeloid Gab1‐specific mutants for OVA challenge. Lung histology and mucus metaplasia indicated that disruption of Gab1 in DCs leads to alleviated asthmatic inflammation, characterized by marked reduction of Th2 cytokines, inflammatory cell infiltration, and mucus production. Together, these findings have implications for the pathogenesis and therapy of asthma.