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CISH 损害活化 T 细胞中的溶酶体功能，导致线粒体 DNA 释放和炎症老化。

CISH impairs lysosomal function in activated T cells resulting in mitochondrial DNA release and inflammaging.

机构信息

Multiscale Research Institute for Complex Systems, Fudan University, Shanghai, China.

Department of Immunology, Mayo Clinic, Rochester, MN, USA.

出版信息

Nat Aging. 2023 May;3(5):600-616. doi: 10.1038/s43587-023-00399-w. Epub 2023 Apr 17.

DOI:10.1038/s43587-023-00399-w
PMID:37118554
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10388378/
Abstract

Chronic systemic inflammation is one of the hallmarks of the aging immune system. Here we show that activated T cells from older adults contribute to inflammaging by releasing mitochondrial DNA (mtDNA) into their environment due to an increased expression of the cytokine-inducible SH2-containing protein (CISH). CISH targets ATP6V1A, an essential component of the proton pump V-ATPase, for proteasomal degradation, thereby impairing lysosomal function. Impaired lysosomal activity caused intracellular accumulation of multivesicular bodies and amphisomes and the export of their cargos, including mtDNA. CISH silencing in T cells from older adults restored lysosomal activity and prevented amphisomal release. In antigen-specific responses in vivo, CISH-deficient CD4 T cells released less mtDNA and induced fewer inflammatory cytokines. Attenuating CISH expression may present a promising strategy to reduce inflammation in an immune response of older individuals.

摘要

慢性系统性炎症是衰老免疫系统的特征之一。在这里，我们发现由于细胞因子诱导的含 SH2 蛋白（CISH）的表达增加，老年个体的活化 T 细胞将线粒体 DNA（mtDNA）释放到其环境中，从而导致炎症老化。CISH 将质子泵 V-ATPase 的必需组成部分 ATP6V1A 作为靶标进行蛋白酶体降解，从而损害溶酶体功能。溶酶体功能受损导致多泡体和内体在细胞内积累，并将其货物（包括 mtDNA）输出。在老年个体的 T 细胞中沉默 CISH 可恢复溶酶体活性并防止内体释放。在体内的抗原特异性反应中，CISH 缺陷型 CD4 T 细胞释放的 mtDNA 较少，诱导的炎性细胞因子也较少。抑制 CISH 的表达可能是减少老年个体免疫反应中炎症的一种很有前途的策略。

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