2021-10-28

本期文章：《自然—免疫学》：Online/在线发表

近日，美国密歇根大学Pavan Reddy团队发现，肠道上皮细胞中的线粒体复合体II调节T细胞介导的免疫病理。相关论文于2021年10月22日在线发表于国际学术期刊《自然—免疫学》。

研究人员发现，在T细胞介导结肠炎的几个不同模型中，肠上皮细胞（IEC）的氧化磷酸化被破坏，琥珀酸含量增加。代谢通量研究并结合成像和蛋白质分析确定了IEC内琥珀酸脱氢酶A（SDHA）的破坏，它是线粒体复合体II的一个组成部分，导致了这些代谢改变。研究人员通过互补的化学和遗传实验方法证实了IEC本身的SDHA在介导疾病严重性方面的相关性，并在人类临床样本中得到验证。

这些数据确定了IEC特异性线粒体复合体II成分SDHA的改变在调控T细胞介导肠道疾病严重性的关键作用。

据了解，T细胞对IEC的损伤导致了移植物抗宿主病、炎症性肠病和免疫检查点阻断剂介导的结肠炎。但对影响疾病严重性的靶细胞内在特征知之甚少。

附：英文原文

Title: Mitochondrial complex II in intestinal epithelial cells regulates T cell-mediated immunopathology

Author: Fujiwara, Hideaki, Seike, Keisuke, Brooks, Michael D., Mathew, Anna V., Kovalenko, Ilya, Pal, Anupama, Lee, Ho-Joon, Peltier, Daniel, Kim, Stephanie, Liu, Chen, Oravecz-Wilson, Katherine, Li, Lu, Sun, Yaping, Byun, Jaeman, Maeda, Yoshinobu, Wicha, Max S., Saunders, Thomas L., Rehemtulla, Alnawaz, Lyssiotis, Costas A., Pennathur, Subramaniam, Reddy, Pavan

Issue&Volume: 2021-10-22

Abstract: Intestinal epithelial cell (IEC) damage by T cells contributes to graft-versus-host disease, inflammatory bowel disease and immune checkpoint blockade-mediated colitis. But little is known about the target cell-intrinsic features that affect disease severity. Here we identified disruption of oxidative phosphorylation and an increase in succinate levels in the IECs from several distinct in vivo models of T cell-mediated colitis. Metabolic flux studies, complemented by imaging and protein analyses, identified disruption of IEC-intrinsic succinate dehydrogenase A (SDHA), a component of mitochondrial complex II, in causing these metabolic alterations. The relevance of IEC-intrinsic SDHA in mediating disease severity was confirmed by complementary chemical and genetic experimental approaches and validated in human clinical samples. These data identify a critical role for the alteration of the IEC-specific mitochondrial complex II component SDHA in the regulation of the severity of T cell-mediated intestinal diseases.

DOI: 10.1038/s41590-021-01048-3

期刊信息

Nature Immunology：《自然—免疫学》，创刊于2000年。隶属于施普林格·自然出版集团，最新IF：23.53