Interleukin 31 receptor alpha induces airway hyperresponsiveness in asthma

Abstract

Asthma is a chronic inflammatory airway disease characterized by airway hyperresponsiveness (AHR), inflammation, and goblet cell hyperplasia. Both Th1 and Th2 cytokines, including IFN-{gamma}, IL-4, and IL-13 have been shown to induce asthma; however, the underlying mechanisms remain unclear. We observed a significant increase in the expression of IL-31RA, but not its cognate ligand IL-31 during house dust mite- and Schistosoma mansoni soluble egg antigen-induced allergic asthma. In support of this, IFN-{gamma} and Th2 cytokines, IL-4 and IL-13, upregulated IL-31RA but not IL-31 in airway smooth muscle cells (ASMC). Importantly, the loss of IL-31RA attenuated AHR but had no effects on inflammation and goblet cell hyperplasia in allergic asthma or mice treated with IL-13 or IFN{gamma}. Mechanistically, we demonstrate that IL-31RA functions as a positive regulator of muscarinic acetylcholine receptor 3 (CHRM3) expression and calcium signaling involved in the contractility of ASMC. Together, these results identified a novel role for IL-31RA in ASMC contractility and AHR distinct from airway inflammation and goblet cell hyperplasia in asthma. SummaryThe study identified an important role for the IL-31RA-CHRM3 axis in inducing airway hyperresponsiveness with limited changes in inflammation in allergic asthma. IL-31RA, whose expression is regulated by both Th1 and Th2 cytokines, augments the CHRM3-dependent contractility of ASMC and AHR.