Editors' ChoiceCalcium signaling

SOCE, mitochondria, and inflammation

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Science Signaling  28 May 2019:
Vol. 12, Issue 583, eaay1437
DOI: 10.1126/scisignal.aay1437

Store-operated calcium entry regulates mitochondrial function to support pathogenic TH17 cells and promote inflammation.

T helper 17 (TH17) cells are a subset of CD4+ T cells that secrete the proinflammatory cytokine interleukin-17 (IL-17) and mediate immune responses to bacterial and fungal infections. They are also implicated in autoimmune diseases and chronic inflammatory disorders. TH17 cells are activated through stimulation of the T cell receptor (TCR), which leads to store-operated Ca2+ entry (SOCE) through plasma membrane CRAC channels in a manner dependent on the endoplasmic reticulum (ER)–resident sensor STIM1. Kaufmann et al. found that mice expressing a hyperactive STAT3 mutant specifically in CD4+ T cells (S3CCD4 mice) spontaneously generated TH17 cells and exhibited extensive lung inflammation, whereas mice in which STIM1 was knocked out in these same cells (S1-S3CCD4 mice) had fewer TH17 cells, less IL-17, and less inflammation. Compared with S3CCD4 TH17 cells, S1-S3CCD4 TH17 cells exhibited reduced expression of genes associated with pathogenic TH17 cells; however, both cell types expressed similar amounts of factors required for TH17 cell development. The S1-S3CCD4 TH17 cells showed impaired cell cycle entry and proliferated less efficiently than did their STIM1-sufficient counterparts. In addition, S1-S3CCD4 TH17 cells had reduced expression of many genes encoding components of the mitochondrial electron transport chain, swollen mitochondria, and impaired oxidative phosphorylation (OXPHOS). Furthermore, S1-S3CCD4 TH17 cells exhibited decreased expression of antioxidant genes, which resulted in enhanced reactive oxygen species (ROS) production compared with S3CCD4 TH17 cells. Increased ROS accumulation led to DNA damage and apoptosis of the S1-S3CCD4 TH17 cells. Treatment of pathogenic TH17 cells isolated from the lungs of S3CCD4 mice with the OXPHOS inhibitor oligomycin led to reduced IL-17 production and increased expression of genes associated with nonpathogenic TH17 cells. In a T cell transfer model of colitis, mice that received CD4+ T cells from S3CCD4 mice showed increased weight loss and colonic inflammation compared with mice that received CD4+ T cells from S1-S3CCD4 mice. Together, these findings suggest that STIM1-dependent SOCE is important for regulating mitochondrial function to drive inflammation mediated by pathogenic TH17 cells and that targeting SOCE may be therapeutic in the context of TH17 cell–mediated inflammatory diseases.

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