Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease.
Marilena LetiziaYin-Hu WangUlrike KaufmannLorenz GerbethAnnegret SandMax BrunkhorstPatrick WeidnerJörn Felix ZieglerChotima BöttcherStephan SchlickeiserCamila FernándezMegumi YamashitaKenneth A StaudermanKatherine SunDésirée KunkelMurali Prakriyanull nullAshley D SandersBritta SiegmundStefan FeskeCarl WeidingerPublished in: EMBO molecular medicine (2022)
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 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.
Keyphrases
- immune response
- induced apoptosis
- ulcerative colitis
- cell cycle arrest
- dendritic cells
- rheumatoid arthritis
- oxidative stress
- endothelial cells
- type diabetes
- cell death
- signaling pathway
- gene expression
- adipose tissue
- machine learning
- metabolic syndrome
- insulin resistance
- skeletal muscle
- protein kinase
- electronic health record
- data analysis
- nk cells