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

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

研究成果査読

18 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1440-1451
ページ数12
ジャーナルNature Immunology
22
11
DOI
出版ステータスPublished - 11月 2021

ASJC Scopus subject areas

  • 免疫アレルギー学
  • 免疫学

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