| Autor: |
Endo, Yusuke, Kanno, Toshio, Nakajima, Takahiro, Ikeda, Kazutaka, Taketomi, Yoshitaka, Yokoyama, Satoru, Sasamoto, Shigemi, Asou, Hikari K., Miyako, Keisuke, Hasegawa, Yoshinori, Kawashima, Yusuke, Ohara, Osamu, Murakami, Makoto, Nakayama, Toshinori |
| Zdroj: |
Science Immunology; 2023, Vol. 8 Issue 86, p1-18, 18p |
| Abstrakt: |
Metabolic fluxes involving fatty acid biosynthesis play essential roles in controlling the differentiation of T helper 17 (TH17) cells. However, the exact enzymes and lipid metabolites involved, as well as their link to promoting the core gene transcriptional signature required for the differentiation of TH17 cells, remain largely unknown. From a pooled CRISPR-based screen and unbiased lipidomics analyses, we identified that 1-oleoyl-lysophosphatidylethanolamine could act as a lipid modulator of retinoid-related orphan receptor gamma t (RORγt) activity in TH17 cells. In addition, we specified five enzymes, including Gpam, Gpat3, Lplat1, Pla2g12a, and Scd2, suggestive of the requirement of glycerophospholipids with monounsaturated fatty acids being required for the transcription of Il17a. 1-Oleoyl-lysophosphatidylethanolamine was reduced in Pla2g12a-deficient TH17 cells, leading to the abolition of interleukin-17 (IL-17) production and disruption to the core transcriptional program required for the differentiation of TH17 cells. Furthermore, mice with T cell–specific deficiency of Pla2g12a failed to develop disease in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, our data indicate that 1-oleoyl-lysophosphatidylethanolamine is a lipid metabolite that promotes RORγt-induced TH17 cell differentiation and the pathogenicity of TH17 cells. Editor's summary: Lipid metabolic pathways and the transcription factor RORγt are known to control the differentiation of pro-inflammatory Th17 cells, but direct links between cellular metabolism and the activity of RORγt have not been fully elucidated. Using a combination of gene knockouts and lipidomics, Endo et al. identified a specific lipid metabolite, along with five enzymes required for its biosynthesis, that maintained the Th17 gene expression program. The lipid, called 1-Oleoyl-lysophosphatidylethanolamine, could bind to RORγt directly, and knockout of an orphan phospholipase A2 (PLA2) isoform required for its biosynthesis inhibited the differentiation of murine Th17 cells and protected against pathology driven by Th17 cells in a mouse model of autoimmune encephalomyelitis. This study develops understanding of how metabolic pathways influence T cell differentiation. —Sarah H. Ross [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
|
