The metabolic reprogramming of T cells controls airway remodeling in severe asthma

ABSTRACT: Background: Mixed granulocytic asthma (MGA) is a severe Th2-low endotype, characterized by high Th17/neutrophilic burden and exacerbated airway remodeling. Both features confer resistance to inhaled corticosteroids and typical asthma treatments. Objective: We aimed to address gaps in knowledge, including how Th17 cells induce pathological tissue remodeling and how Th17 differentiation occurs in response to allergens. Methods: We generated a Th2-low murine model of asthma on the Il4rα-/- background that mimics the decrease in type 2 response seen in corticosteroid-resistant patients. We monitored major features of human disease including heightened airway reactivity to methacholine, Th17/neutrophilic inflammation, airway remodeling, and resistance to corticosteroid treatment. Comparative transfer of Th2 versus Th17 cells were analyzed. We further investigated how the mitochondrial oxidative phosphorylation (OXPHOS) pathway modulates pathogenic Th17 cell reprogramming by in vitro T cell cultures and in vivo therapeutic blockades. Results: LIGHT (aka TNFSF14) and the OXPHOS pathway are enriched in human MGA and likewise upregulated in this mouse model. We show OXPHOS promotes the metabolic reprograming of Th17 cells, to sustain their survival despite steroid treatment and produce LIGHT that controls airway remodeling. Mechanistically, OXPHOS regulates RORγt expression and the subsequent transcriptional network to program differentiation of Th17 cells, whereas LIGHT drives airway remodeling by activating the MMP9-dependent TGFβ pathway. Additionally, OXPHOS+Th17 cells promote the expression of osteopontin necessary for fibroblast activation. LIGHT antagonistic blockade reduces airway remodeling, whereas OXPHOS inhibition kills Th17 cells and subsequent neutrophilia. Importantly, the dual blockade of LIGHT and OXPHOS reverses all features of MGA back to baseline and reciprocally increases the numbers of Treg cells. Conclusions: The dual blockade of LIGHT and OXPHOS constitutes a promising target for clinical interventions in human MGA, possibly extending to other Th17-driven fibrotic diseases.

ORGANISM(S): Mus musculus

PROVIDER: GSE352552 | GEO | 2026/10/30

REPOSITORIES: GEO