钙内流调节IBD相关的免疫细胞功能
创作:阿童木 审核:aluba 2022年08月16日
  • IBD患者结肠固有层的CD4+ T细胞、CD8+ T细胞、调节性T细胞(Treg)及天然淋巴细胞(ILC)富集;
  • 药物抑制SOCE可抑制人结肠T细胞及ILC产生IL-2、IL-4、IL-6、IL-17A、TNF及IFN-γ,抑制B细胞产生IL-6,抑制髓系细胞产生IFN-γ,但不影响肠道上皮细胞的存活、分化及功能;
  • T细胞特异性敲除CRAC通道基因(Orai1、Stim1、Stim2)可抑制Th1细胞及Th17细胞的细胞因子产生;
  • 药物抑制SOCE或T细胞特异性敲除CRAC通道基因可缓解小鼠结肠炎。
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aluba
钙池操控钙内流(SOCE)可诱导钙离子释放激活钙离子(CRAC)通道的开放,从而激活免疫细胞。EMBO Molecular Medicine上发表的一项最新研究结果,发现药物抑制SOCE可降低T细胞、ILC、B细胞及髓系细胞的促炎因子产生,而药物抑制SOCE或T细胞特异性敲除CRAC基因可缓解小鼠结肠炎。
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Store-operated calcium entry controls innate and adaptive immune cell function in inflammatory bowel disease

钙池操控钙内流调节IBD相关的先天性和适应性免疫细胞功能

10.15252/emmm.202215687

2022-08-02, Article

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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.

First Authors:
Marilena Letizia,Yin-Hu Wang,Ulrike Kaufmann

Correspondence Authors:
Stefan Feske,Carl Weidinger

All Authors:
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

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