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Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease

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Item Type:Article
Title:Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease
Creators Name:Letizia, M. and Wang, Y.H. and Kaufmann, U. and Gerbeth, L. and Sand, A. and Brunkhorst, M. and Weidner, P. and Ziegler, J.F. and Böttcher, C. and Schlickeiser, S. and Fernández, C. and Yamashita, M. and Stauderman, K. and Sun, K. and Kunkel, D. and Prakriya, M. and Sanders, A.D. and Siegmund, B. and Feske, S. and Weidinger, C.
Abstract: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 CD(4+) effector T cells producing IL-17A and TNF, CD(8+) T cells producing IFNγ, T regulatory (Treg) cells, and innate lymphoid cells (ILC). The function of these immune cells is regulated by store-operated Ca(2+) entry (SOCE), which results from the opening of Ca(2+) release-activated Ca(2+) (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.
Keywords:Crohn's Disease, Mass Cytometry, Store-Operated Calcium Entry (SOCE), T Cell Transfer Models of Colitis, Ulcerative Colitis, Animals, Mice
Source:EMBO Molecular Medicine
ISSN:1757-4676
Publisher:EMBO Press
Page Range:e15687
Date:2 August 2022
Official Publication:https://doi.org/10.15252/emmm.202215687
PubMed:View item in PubMed

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