Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease
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Inflammatory bowel disease (IBD) is characterized by dysregulated intestinal immune responses. Using mass cytometry (CyTOF) to analyze the immune cell composition in the lamina propria (LP) of patients with ulcerative colitis (UC) and Crohn's disease (CD), we observed an enrichment of CD4+ effector T cells producing IL-17A and TNF, CD8+ T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca2+ entry (SOCE), which results from the opening of Ca2+ release-activated Ca2+ (CRAC) channels formed by ORAI and STIM proteins. We observed that the pharmacologic inhibition of SOCE attenuated the production of proinflammatory cytokines including IL-2, IL-4, IL-6, IL-17A, TNF, and IFNγ by human colonic T cells and ILCs, reduced the production of IL-6 by B cells and the production of IFNγ by myeloid cells, but had no effect on the viability, differentiation, and function of intestinal epithelial cells. T cell-specific deletion of CRAC channel genes in mice showed that Orai1, Stim1, and Stim2-deficient T cells have quantitatively distinct defects in SOCE, which correlate with gradually more pronounced impairment of cytokine production by Th1 and Th17 cells and the severity of IBD. Moreover, the pharmacologic inhibition of SOCE with a selective CRAC channel inhibitor attenuated IBD severity and colitogenic T cell function in mice. Our data indicate that SOCE inhibition may be a suitable new approach for the treatment of IBD.
Marilena Letizia,Yin-Hu Wang,Ulrike Kaufmann
Stefan Feske,Carl Weidinger
Marilena Letizia,Yin-Hu Wang,Ulrike Kaufmann,Lorenz Gerbeth,Annegret Sand,Max Brunkhorst,Patrick Weidner,Jörn Felix Ziegler,Chotima Böttcher,Stephan Schlickeiser,Camila Fernández,Megumi Yamashita,Kenneth Stauderman,Katherine Sun,Désirée Kunkel,Murali Prakriya,IBDome Researchers,Ashley D Sanders,Britta Siegmund,Stefan Feske,Carl Weidinger