Fatty Acid Oxidation Promotes Apoptotic Resistance and Proinflammatory Phenotype of CD4+ Tissue-resident Memory T cells in Crohn’s Disease

Abstract

Background and aimsAs the most abundant memory T cells and major source of tumor necrosis factor α (TNF-α) in the intestinal mucosa of Crohn’s disease (CD) patients, CD4+ tissue-resident memory T (TRM) cells play a critical role in CD pathogenesis. We investigated the role of metabolic reprogramming in the regulation of proinflammatory and apoptosis-resistant phenotype for CD4+ TRM cells. MethodsCD4+ TRM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4+ TRM cells. ELISA and qPCR experiments were utilized to assess cytokines level in CD4+ TRM cells, activation-induced cell apoptosis (AICD) rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4+ TRM cells on the migration of normal intestinal epithelial cells. ResultsTranscriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4+ TRM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4+ TRM cells upregulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated NF-κB signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake and oxidation in CD4+ TRM cells from CD patients. Targeting FAO of CD4+ TRM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD Patients. ConclusionCD4+ TRM cells process an accelerated FAO mediated by activated NF-κB signaling in CD patients, targeting FAO could reverse their apoptosis-resistant and proinflammatory phenotype. These findings shed a new light on the pathogenic mechanism investigation and novel therapy development in CD patients.