The role of the PAR2‐beta‐arrestin signaling axis in Alternaria and cockroach‐induced allergic asthma (934.3)

Abstract

A common cause of asthma is the exposure to allergens such as the household fungus, Alternaria alternata (AltA), and the feces of the common cockroach, Blattella germanica (BG), which contain proteases that activate Protease‐activated‐receptor‐2 (PAR2). In several murine models of asthma, PAR2 activation has been shown to be pro‐ and anti‐inflammatory. Recently, our lab has shown that the pro‐inflammatory pathway is mediated by beta‐arrestins, which act as both terminators of GPCR signaling through G‐proteins, and as scaffolding proteins that signal independently of G‐proteins. In contrast, the anti‐inflammatory pathway requires G‐protein signaling. We hypothesize that proteases from AltA and BG extracts will promote activation of the beta‐arrestin‐2 dependent inflammatory pathway in murine models that we have previously observed with intranasal administration of Par2 peptidomimetic agonists. Here, we have performed flow cytometric analyses of immune cell populations and analyzed histological samples in physiological mouse models of AltA and BG‐induced allergic asthma. Our results show that airway inflammation induced by AltA and BG are abolished in beta‐arresitn‐2‐/‐ and PAR2‐/‐ mice. Furthermore, AltA and BG proteases activate downstream signaling mechanisms in a beta‐arrestin‐2‐dependent way. This suggests that the proteases can activate the PAR2‐beta‐arrestin signaling axis, which in turn regulates immunological responses in the airway.