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 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.
| Original language | English (US) |
|---|---|
| Article number | e15687 |
| Journal | EMBO Molecular Medicine |
| Volume | 14 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 7 2022 |
Funding
We would like to acknowledge the assistance of the BIH Cytometry Core (BIH and Charité – Universitätsmedizin Berlin, Germany) and the IBDome researchers Chiara Romagnani, Nils Müller, Ahmed Hegazy, Roodline Cineus, Julia Hecker, Nadine Sommer, and Anja Kühl for supporting the isolation and processing of surgical specimen. This work was funded by the German Research Foundation (We 5303/3‐1 to CW, Si 749/10‐1 to BS, SFB‐TRR 241 B01 to BS and CW, SFB TRR167 B05 to CB) and NIH grants AI097302, AI130143 and AI137004 (to SF), a Senior Research Award by the Crohn's and Colitis Foundation of America (to SF) and an Irma T. Hirschl career scientist award (to SF). MB and JFZ received financial support from the Einstein Foundation Berlin. CW received funding by the Clinician Scientist Program of the Berlin Institute of Health and by the Fritz‐Thyssen‐Foundation (10.19.2.028MN). Open Access funding enabled and organized by Projekt DEAL. WOA Institution: Charite Universitatsmedizin Berlin. Consortia Name: Projekt DEAL. We would like to acknowledge the assistance of the BIH Cytometry Core (BIH and Charité – Universitätsmedizin Berlin, Germany) and the IBDome researchers Chiara Romagnani, Nils Müller, Ahmed Hegazy, Roodline Cineus, Julia Hecker, Nadine Sommer, and Anja Kühl for supporting the isolation and processing of surgical specimen. This work was funded by the German Research Foundation (We 5303/3-1 to CW, Si 749/10-1 to BS, SFB-TRR 241 B01 to BS and CW, SFB TRR167 B05 to CB) and NIH grants AI097302, AI130143 and AI137004 (to SF), a Senior Research Award by the Crohn's and Colitis Foundation of America (to SF) and an Irma T. Hirschl career scientist award (to SF). MB and JFZ received financial support from the Einstein Foundation Berlin. CW received funding by the Clinician Scientist Program of the Berlin Institute of Health and by the Fritz-Thyssen-Foundation (10.19.2.028MN). Open Access funding enabled and organized by Projekt DEAL. WOA Institution: Charite Universitatsmedizin Berlin. Consortia Name: Projekt DEAL.
Keywords
- Crohn's disease
- T cell transfer models of colitis
- mass cytometry
- store-operated calcium entry (SOCE)
- ulcerative colitis
ASJC Scopus subject areas
- Molecular Medicine
