Myeloid cAMP is required to drive neutrophilic airway inflammation in asthma exacerbation after rhinovirus infection 2304

Abstract Description Asthma exacerbations, which result from human rhinovirus (hRV) infection, are characterized by airway neutrophilia and reduced response to corticosteroid treatment, contributing to significant healthcare expenditure and functional impairment of the lungs. The Gas subunit of the trimeric G protein is essential in the regulation of multiple immunopathological diseases by modulating cAMP levels. Here, we deleted Gnas, the gene of Gas, in myeloid cells with targeting LysM (GnasDLysM mice), and found that loss of myeloid Gas resulted in a striking shift of airway inflammation from a neutrophilic to an eosinophilic phenotype during asthma exacerbation caused by hRV infection. Myeloid Gas-ablated mice showed hypersecretion of mucus and Th2-type inflammation in Th17-type allergen-induced asthmatic disease by hRV infection, along with enhanced differentiation of CD4+ Th2 effector cells. Myeloid Gas deficiency was found to hinder the activation of NLRP3 inflammasome, thereby suppressing M1 polarization of interstitial macrophages in the context of eosinophilic airway inflammation. Furthermore, our results were established a link between cAMP levels in macrophages and M1 polarization. Therefore, these findings suggest that cAMP levels in macrophages play a pivotal role in eliciting steroid-resistant, neutrophil-dominated airway inflammation during asthma exacerbation triggered by hRV infection. Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)