Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation

Meng X, Asadi Asadabad S, Cao S, Song R, Lin Z, Safhi M, Qin Y, Tcheumi Tactoum EM, Taudte V, Ekici AB, Mielenz D, Wirtz S, Schett G, Bozec A (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Cellular & Molecular Immunology Nature Publishing Group: Open Access Hybrid Model Option A

DOI: 10.1038/s41423-024-01233-y

Abstract

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

Authors with CRIS profile

Xianyi Meng Sahar Asadi Asadabad Department of Medicine 3 – Rheumatology and Immunology Shan Cao Rui Song Department of Medicine 3 – Rheumatology and Immunology Zhen Lin Professur für Experimentelle Immuntherapie Mohammed Safhi Lehrstuhl für Genetik Yi Qin Lehrstuhl für Genetik Estelle Manuella Tcheumi Tactoum Department of Medicine 3 – Rheumatology and Immunology Verena Taudte Lehrstuhl für Klinische Pharmakologie und Klinische Toxikologie Arif Bülent Ekici Institute of Human Genetics Dirk Mielenz Medizinische Fakultät Stefan Wirtz Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Georg Schett Lehrstuhl für Innere Medizin III Aline Bozec

How to cite

APA:

Meng, X., Asadi Asadabad, S., Cao, S., Song, R., Lin, Z., Safhi, M.,... Bozec, A. (2024). Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation. Cellular & Molecular Immunology. https://doi.org/10.1038/s41423-024-01233-y

MLA:

Meng, Xianyi, et al. "Metabolic rewiring controlled by HIF-1α tunes IgA-producing B-cell differentiation and intestinal inflammation." Cellular & Molecular Immunology (2024).

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