Myeloid cAMP Reduction Shifts Rhinovirus-Induced Airway Inflammation From Neutrophilic to Eosinophilic by Suppressing M1-Interstitial Macrophages

Abstract

Background: Asthma exacerbations caused by human rhinovirus (hRV) infection are characterized by airway neutrophilia and reduced corticosteroid response, leading to significant healthcare costs and lung function impairment. The Gαs subunit of the trimeric G protein regulates immunopathological conditions by modulating cAMP levels. We aimed to investigate the impact of myeloid cAMP levels on neutrophil-dominated asthma exacerbation caused by hRV infection.

Methods: We generated mice with myeloid cell-specific deletion of the Gαs subunit by targeting the LysM gene, leading to a specific reduction of cAMP in myeloid cells. Neutrophilic asthma exacerbation was induced by hRV infection during allergen challenge, and cytokine production in BALF and lung tissue was assessed, along with histological examinations.

Results: Myeloid Gαs ablation was found to shift airway inflammation from a neutrophilic to an eosinophilic phenotype during hRV-induced asthma exacerbation. This change led to mucus hypersecretion and Th2-type inflammation, and enhanced CD4⁺ Th2 effector cell expansion. In chronic asthma with repeated allergen and hRV exposure, myeloid Gαs ablation caused mixed Th2- and Th17-biased inflammation with increased neutrophil and eosinophil infiltration and collagen deposition. Myeloid Gαs deficiency hindered NLRP3 inflammasome activation, thereby suppressing M1 polarization of interstitial macrophages during eosinophilic inflammation. cAMP levels in macrophages were likely associated with M1 polarization, as cAMP analogs regulated NLRP3 inflammasome activation via PKA and EPAC pathways. Finally, adoptive transfer of cAMP analog-treated macrophages reversed eosinophilic to neutrophilic inflammation in myeloid Gαs-ablated mice following hRV infection.

Conclusions: These results highlight the essential role of macrophage cAMP in steroid-resistant, neutrophil-dominant airway inflammation during hRV-induced asthma exacerbation.

Keywords: asthma exacerbation; cAMP; human rhinovirus; inflammasome; macrophage polarization.