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STIM1 介导体钙内流控制抗真菌免疫和非致病性 Th17 细胞的代谢功能。

STIM1-mediated calcium influx controls antifungal immunity and the metabolic function of non-pathogenic Th17 cells.

机构信息

Department of Pathology, New York University Grossman School of Medicine, New York, NY, USA.

The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.

出版信息

EMBO Mol Med. 2020 Aug 7;12(8):e11592. doi: 10.15252/emmm.201911592. Epub 2020 Jul 1.

DOI:10.15252/emmm.201911592
PMID:32609955
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7411566/
Abstract

Immunity to fungal infections is mediated by cells of the innate and adaptive immune system including Th17 cells. Ca influx in immune cells is regulated by stromal interaction molecule 1 (STIM1) and its activation of the Ca channel ORAI1. We here identify patients with a novel mutation in STIM1 (p.L374P) that abolished Ca influx and resulted in increased susceptibility to fungal and other infections. In mice, deletion of STIM1 in all immune cells enhanced susceptibility to mucosal C. albicans infection, whereas T cell-specific deletion of STIM1 impaired immunity to systemic C. albicans infection. STIM1 deletion impaired the production of Th17 cytokines essential for antifungal immunity and compromised the expression of genes in several metabolic pathways including Foxo and HIF1α signaling that regulate glycolysis and oxidative phosphorylation (OXPHOS). Our study further revealed distinct roles of STIM1 in regulating transcription and metabolic programs in non-pathogenic Th17 cells compared to pathogenic, proinflammatory Th17 cells, a finding that may potentially be exploited for the treatment of Th17 cell-mediated inflammatory diseases.

摘要

对真菌感染的免疫是由先天和适应性免疫系统的细胞介导的，包括 Th17 细胞。免疫细胞中的钙内流受基质相互作用分子 1（STIM1）及其激活钙通道 ORAI1 调节。我们在这里鉴定了具有 STIM1 新突变（p.L374P）的患者，该突变消除了钙内流，导致对真菌和其他感染的易感性增加。在小鼠中，所有免疫细胞中 STIM1 的缺失增强了对粘膜白色念珠菌感染的易感性，而 T 细胞特异性缺失 STIM1 则损害了对系统性白色念珠菌感染的免疫力。STIM1 的缺失损害了对抗真菌免疫至关重要的 Th17 细胞因子的产生，并损害了包括 Foxo 和 HIF1α 信号在内的几个代谢途径中的基因表达，这些途径调节糖酵解和氧化磷酸化（OXPHOS）。我们的研究进一步揭示了 STIM1 在调节非致病性 Th17 细胞和致病性、促炎 Th17 细胞转录和代谢程序方面的不同作用，这一发现可能为治疗 Th17 细胞介导的炎症性疾病提供潜在的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bac1/7411566/0ce92753897f/EMMM-12-e11592-g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bac1/7411566/9eb121c42f03/EMMM-12-e11592-g010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bac1/7411566/2641ce1d6541/EMMM-12-e11592-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/bac1/7411566/0454e0ba96cd/EMMM-12-e11592-g012.jpg
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