FFAR2/3 dysfunction aggravates IL-33-induced eosinophilic airway inflammation via ST2+CD4+ T cell activation

Short-chain fatty acids (SCFAs) are metabolites produced by the gut microbiota that have immunomodulatory effects and are implicated in various diseases, including asthma. However, the precise molecular mechanisms underlying the role of SCFAs in asthma pathogenesis remain unclear. We aimed to investigate the role of the SCFA receptors FFAR2 and FFAR3 in a mouse model of IL-33-induced eosinophilic airway inflammation. Intranasal IL-33 administration decreased propionate, an SCFA that serves as a ligand for FFAR2 and FFAR3. In Ffar2/Ffar3-deficient mice, intranasal IL-33 administration activated ILC2s, as in wild-type mice. However, it prominently activated ST2+CD4+ T cells, resulting in increased type 2 cytokine levels and aggravated eosinophilic airway inflammation compared with wild-type mice. Furthermore, propionate regulates CD4+ T cell activity and mitigates IL-33-induced eosinophilic inflammation. These results suggest that the propionate-CD4+ T-cell axis could be a therapeutic target for asthma.