B cell metabolic anomalies contribute to the pathogenesis of Crohn’s disease-like ileitis in SAMP1/YitFcs Mice 4566

Abstract Description Background SAMP mice are a model of Crohn’s disease (CD) with spontaneous terminal ileitis initiated by an effector T cell response and worsened by B cell response. Cell metabolic rewiring towards glycolysis being a hallmark of immune cell activation, we aimed to uncover how T and B cell metabolism is altered in SAMP mice. Results RNA sequencing analysis from ileum scraping revealed a remarkable activation of all catabolic pathways, especially glycolysis. Key glycolysis-related genes were found to be highly upregulated, such as HIF-1α, Hexokinase and GLUT-1. In-situ glucose metabolism was assessed using 18F-FDG PET imaging that spotted ileum, salivary glands and kidney as tissues taking up glucose; each exhibiting evidence of inflammation and infiltration of GLUT-1+ cells. Mesenteric lymph node-isolated SAMP B cells, but not T cells, showed a higher plasma membrane expression of GLUT-1 coupled to a greater capacity to undergo glycolysis, and caused extraintestinal inflammation in an adoptive transfer model of ileitis. Inhibition of cell metabolism in vivo reduced ileitis and alleviated kidney inflammation in SAMP mice. Conclusion Our findings identified a unique metabolic signature and an abnormal B cell metabolic phenotype relying on a facilitated GLUT1-mediated switch to glycolysis, associated with SAMP pathology. Targeting B cell glucose metabolism could offer a novel therapeutic approach for CD patients by controlling both intestinal and extra-intestinal inflammation. Funding Sources supported by the National Institutes of Health (NIH) under Award NIH RO1-AI079145, NIH P30-DK 120515, DKT32-007202, and the Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccine Development. Topic Categories Immune Mechanisms of Human Disease (HUM)