Citation

Germinal centers where B cells undergo clonal expansion and antibody affinity maturation are hypoxic microenvironments. However, the function of hypoxia-inducible factor (HIF)-1? in immunoglobulin production remains incompletely characterized. Here, we demonstrated that B cells lacking HIF-1? exhibited significantly lower glycolytic metabolism and impaired IgA production. Loss of HIF-1? in B cells affects IgA-producing B-cell differentiation and exacerbates dextran sodium sulfate (DSS)-induced colitis. Conversely, promoting HIF-1? stabilization via a PHD inhibitor roxadustat enhances IgA class switching and alleviates intestinal inflammation. Mechanistically, HIF-1? facilitates IgA class switching through acetyl-coenzyme A (acetyl-CoA) accumulation, which is essential for histone H3K27 acetylation at the S? region. Consequently, supplementation with acetyl-CoA improved defective IgA production in Hif1a-deficient B cells and limited experimental colitis. Collectively, these findings highlight the critical importance of HIF-1? in IgA class switching and the potential for targeting the HIF-1?-dependent metabolic?epigenetic axis to treat inflammatory bowel diseases and other inflammatory disorders.