近日，美国国家环境健康科学研究所Michael B. Fessler、Prashant Rai等研究人员合作发现，IRGM1可将线粒体质量控制与自身免疫联系起来。相关论文于2021年1月28日在线发表在《自然—免疫学》杂志上。

研究人员认为无法通过线粒体自噬清除缺陷的线粒体可能是通过线粒体DNA依赖型I型干扰素来诱导出自身免疫。研究人员发现，缺少GTP酶IRGM1（IRGM同源物）的小鼠表现出具有自身免疫特征的I型干扰素病理。Irgm1敲除会损害线粒体自噬的执行，并产生特定于细胞的后果。

在成纤维细胞中，细胞质中的线粒体DNA污染能够诱导环cGAS-STING依赖性I型干扰素；而在巨噬细胞中，溶酶体Toll样受体7被激活。在体内，Irgm1^-/-组织对核酸受体表现出镶嵌依赖性。而唾液和泪腺自身免疫病理被阻止，并且cGAS和STING缺失使肺部病理减弱，而胰腺病理保持不变。这些发现揭示了线粒体质量控制与组织选择性自身免疫病之间的基本联系。

据介绍，狼疮中已发现线粒体异常，但其原因和后果仍然不清楚。自噬相关基因ATG5、ATG7和IRGM已被发现与自身免疫性疾病有关。

附：英文原文

Title: IRGM1 links mitochondrial quality control to autoimmunity

Author: Prashant Rai, Kyathanahalli S. Janardhan, Julie Meacham, Jennifer H. Madenspacher, Wan-Chi Lin, Peer W. F. Karmaus, Jennifer Martinez, Quan-Zhen Li, Mei Yan, Jialiu Zeng, Mark W. Grinstaff, Orian S. Shirihai, Gregory A. Taylor, Michael B. Fessler

Issue&Volume: 2021-01-28

Abstract: Mitochondrial abnormalities have been noted in lupus, but the causes and consequences remain obscure. Autophagy-related genes ATG5, ATG7 and IRGM have been previously implicated in autoimmune disease. We reasoned that failure to clear defective mitochondria via mitophagy might be a foundational driver in autoimmunity by licensing mitochondrial DNA–dependent induction of type I interferon. Here, we show that mice lacking the GTPase IRGM1 (IRGM homolog) exhibited a type I interferonopathy with autoimmune features. Irgm1 deletion impaired the execution of mitophagy with cell-specific consequences. In fibroblasts, mitochondrial DNA soiling of the cytosol induced cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING)-dependent type I interferon, whereas in macrophages, lysosomal Toll-like receptor 7 was activated. In vivo, Irgm1–/– tissues exhibited mosaic dependency upon nucleic acid receptors. Whereas salivary and lacrimal gland autoimmune pathology was abolished and lung pathology was attenuated by cGAS and STING deletion, pancreatic pathology remained unchanged. These findings reveal fundamental connections between mitochondrial quality control and tissue-selective autoimmune disease.

DOI: 10.1038/s41590-020-00859-0

Source: https://www.nature.com/articles/s41590-020-00859-0