Glucose oxidation-dependent survival of activated B cells provides a putative novel therapeutic target for lupus treatment.

Autor:	Wilson JJ; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Wei J; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA.; Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shandong University, Jinan, Shandong 250012, China., Daamen AR; AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA., Sears JD; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA.; Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599, USA., Bechtel E; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Mayberry CL; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Stafford GA; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Bechtold L; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Grammer AC; AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA., Lipsky PE; AMPEL BioSolutions and the RILITE Research Institute, Charlottesville, VA 22902, USA., Roopenian DC; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA., Chang CH; The Jackson Laboratory, Bar Harbor, Maine, ME 04609, USA.; Graduate School of Biomedical Sciences and Engineering, University of Maine, Orono, ME 04469, USA.; Graduate School of Biomedical Sciences, Tufts University School of Medicine, Boston, MA 02111, USA.
Jazyk:	angličtina
Zdroj:	IScience [iScience] 2023 Jul 27; Vol. 26 (9), pp. 107487. Date of Electronic Publication: 2023 Jul 27 (Print Publication: 2023).
DOI:	10.1016/j.isci.2023.107487
Abstrakt:	Aberrant metabolic demand is observed in immune/inflammatory disorders, yet the role in pathogenesis remains unclear. Here, we discover that in lupus, activated B cells, including germinal center B (GCB) cells, have remarkably high glycolytic requirement for survival over T cell populations, as demonstrated by increased metabolic activity in lupus-activated B cells compared to immunization-induced cells. The augmented reliance on glucose oxidation makes GCB cells vulnerable to mitochondrial ROS-induced oxidative stress and apoptosis. Short-term glycolysis inhibition selectively reduces pathogenic activated B in lupus-prone mice, extending their lifespan, without affecting T follicular helper cells. Particularly, BCMA-expressing GCB cells rely heavily on glucose oxidation. Depleting BCMA-expressing activated B cells with APRIL-based CAR-T cells significantly prolongs the lifespan of mice with severe autoimmune disease. These results reveal that glycolysis-dependent activated B and GCB cells, especially those expressing BCMA, are potentially key lupus mediators, and could be targeted to improve disease outcomes. Competing Interests: Authors declare that they have no competing interests. (© 2023 The Authors.)
Databáze:	MEDLINE
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