Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis
Presentation Time: -
Poster Board Number: B535
Abstract ID: 5270
Presenting Author:
Yufeng Zhou , Prof at Fudan Univ.
Abstract:
Objective: To investigate the role of AhR in modulating the functions of macrophages in inflammatory bowel disease (IBD).
Methods: The cellular composition of intestinal lamina propria CD45+ leukocytes in a mouse colitis model was determined by single-cell RNA sequencing. Macrophage pyroptosis and mechanisms were determined by analysis of LDH release, propidium iodide staining, western blot, flow cytometry, RNA-seq etc.
Results: AhR deficiency mediated dynamic remodeling of the cellular composition of intestinal lamina propria (LP) CD45+ immune cells in a colitis model, with a significant increase in monocyte-macrophage lineage. Mice with AhR deficiency in myeloid cells developed more severe DSS induced colitis, with concomitant increased macrophage pyroptosis. Dietary supplementation with an AhR pre-ligand, indole-3-carbinol, conferred protection against colitis while protection failed in mice lacking AhR in myeloid cells. Mechanistically, AhR signaling inhibited macrophage pyroptosis by promoting ornithine decarboxylase 1 (Odc1) transcription, to enhance polyamine biosynthesis. The increased polyamine, particularly spermine, inhibited NLRP3 inflammasome assembly and subsequent pyroptosis by suppressing K+ efflux. AHR expression was positively correlated with ODC1 in intestinal mucosal biopsies from patients with ulcerative colitis.
Conclusions: These findings suggest a functional role for the AhR/ODC1/polyamine axis in maintain intestinal homeostasis.
Aryl hydrocarbon receptor confers protection against macrophage pyroptosis and intestinal inflammation through regulating polyamine biosynthesis
Category
Poster and Podium (Block Symposium)