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Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

ABSTRACT: Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results from their limited capacity to increase glycolysis in response to metabolic stresses. This metabolic program is observed in mouse and human Th17 cells, including those isolated from Crohn disease patients, and it is linked to disease, as inhibiting OXPHOS reduces the severity of murine colitis and psoriasis. These studies highlight the importance of analyzing metabolism in effector lymphocytes within in vivo inflammatory contexts and suggest a therapeutic role for manipulating OXPHOS in Th17-driven diseases.

SUBMITTER: Franchi L

PROVIDER: S-EPMC5360504 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

Franchi Luigi L Monteleone Ivan I Hao Ling-Yang LY Spahr Mark A MA Zhao Wenpu W Liu Xikui X Demock Kellie K Kulkarni Aditi A Lesch Chuck A CA Sanchez Brian B Carter Laura L Marafini Irene I Hu Xiao X Mashadova Oksana O Yuan Min M Asara John M JM Singh Harinder H Lyssiotis Costas A CA Monteleone Giovanni G Opipari Anthony W AW Glick Gary D GD

Journal of immunology (Baltimore, Md. : 1950) 20170227 7

Integration of signaling and metabolic pathways enables and sustains lymphocyte function. Whereas metabolic changes occurring during T cell activation are well characterized, the metabolic demands of differentiated T lymphocytes are largely unexplored. In this study, we defined the bioenergetics of Th17 effector cells generated in vivo. These cells depend on oxidative phosphorylation (OXPHOS) for energy and cytokine production. Mechanistically, the essential role of OXPHOS in Th17 cells results ...[more]

PMID: 28242647

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Project description:Background and aimsInflammatory bowel disease (IBD) places a heavy medical burden on countries and families due to repeated and prolonged attacks, and the incidence and prevalence of IBD are increasing worldwide. Therefore, finding an effective treatment is a matter of great urgency. Glycerol monolaurate (GML), which has a twelve-carbon chain, is a compound naturally found in human breast milk. Some studies have shown that GML has antibacterial and anti-inflammatory effects. However, the specific mechanism of action remains unclear.MethodsAcute colitis was established in mice using 3% DSS, and glycerol monolaurate (500 mg·kg-1) was administered for two weeks. QPCR and western blotting were performed to examine the inflammatory status. Mice described were subjected to flow cytometry analysis for immune cell activation.ResultsGML treated alleviated macroscopic symptoms such as shortened colons, increased spleen weight, and caused weight loss in mice with DSS-induced colitis. In addition, GML decreased the expression of pro-inflammatory factors (NF-α, IL-1β and IL-1α) and increased the expression of anti-inflammatory factors (IL-10 and TGF-β). GML inhibited the activation of the MAPK and NF-κB signalling pathways, improved tissue damage, and increased the expression of intestinal tight junction proteins. In addition, LPMCs extracted from intestinal tissue via flow cytometry showed that GML treatment led to a decrease of Th17 cells, Neutrophils and Macrophages. 16S rDNA sequencing showed that GML increased the abundance of commensal bacterium such as Akkermansia and Lactobacillus murinus.ConclusionsWe showed that oral administration of GML ameliorated DSS-induced colitis by inhibiting infiltration of Th17 cells, Neutrophils, and Macrophages, protecting the intestinal mucosal barrier and altered the abundance of commensal bacterium. This study provides new insights into the biological function and therapeutic potential of GML in the treatment of IBD.

Dataset Information

Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

Publications

Inhibiting Oxidative Phosphorylation In Vivo Restrains Th17 Effector Responses and Ameliorates Murine Colitis.

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