Metabolic reprogramming of Th17 cells drives airway remodeling in severe asthma 2051

Abstract Description Severe asthma (SA) is characterized by a high Th17/neutrophilic burden and an exacerbated airway remodeling. Notably, both airway neutrophilia and remodeling confer resistance to inhaled corticosteroids. Therefore, understanding the unique immune pathogenesis of SA has enormous public health and therapeutic impact. Two biomarkers enriched in human SA, the TNF superfamily member 14 (aka LIGHT), and the mitochondrial oxidative phosphorylation (OXPHOS) pathway, were upregulated in our novel murine SA model. We show that SA is induced by the pathobiological synergy: OXPHOS promotes Th17, while LIGHT controls airway remodeling. Further, OXPHOS regulates RORγt expression to program Th17 cells, whereas LIGHT drives fibrosis by activating the MMP9-dependent TGFβ pathway. OXPHOS and LIGHT synergize together, with OXPHOS+Th17 cells promoting the expression of osteopontin and CXCL12 necessary for fibroblast recruitment and activation, and LIGHT driving IL23 expression. LIGHT antagonistic blockade reduces airway remodeling, whereas OXPHOS chemical inhibition reduces Th17 cells and associated neutrophilia, reciprocal to an increase in Treg cells in SA. Importantly, the dual blockade of LIGHT and OXPHOS abrogates all features of SA, namely airway remodeling, Th17 and associated neutrophilia, in addition to airway hyper-reactivity. The dual blockade of LIGHT and OXPHOS constitutes a promising target for clinical interventions in human severe SA Funding Sources RO1AI177359 from NIAID Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)