Fatty Acid Oxidation Promotes Apoptotic Resistance and Proinflammatory Phenotype of CD4+ Tissue-resident Memory T cells in Crohn’s Disease
Guanzhan Liang, Junfeng Huang, Jing Chen, Xiaofeng Wen, Ruibin Li, Hanlin Xie, Zongjin Zhang, Zexian Chen, Yongle Chen, Zhenyu Xian, Xiaowen He, Jia Ke, Lei Lian, Ping Lan, Xianrui Wu, Tuo Hu
Abstract
Background & Aims As the most abundant memory T cells and major source of tumor necrosis factor α in the intestinal mucosa of Crohn's disease (CD) patients, CD4 + tissue-resident memory T (T RM ) 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 + T RM cells. Methods CD4 + T RM cells were collected from intestinal resection tissues from control and CD patients. Transcriptomic and metabolomic analysis were performed to identify metabolic characteristics of CD4 + T RM cells. Enzyme-linked immunosorbent assay and quantitative polymerase chain reaction experiments were used to assess cytokines level in CD4 + T RM cells; activation-induced cell apoptosis rate was evaluated by flow cytometry. Transwell assay and wound healing assay were performed to detect the effect of CD4 + T RM cells on the migration of normal intestinal epithelial cells. Results Transcriptomic data combined with unbiased metabolomic analysis revealed an increased fatty acid oxidation (FAO) phenotype existed in CD4 + T RM cells from CD patients. The lipidomic data and stable isotope tracer experiments demonstrated that CD4 + T RM cells up-regulated their lipid lipolysis and fatty acid uptake to fuel FAO in CD patients. Mechanistically, the activated nuclear factor kappa B signaling increased transcription of genes involved in lipid lipolysis, fatty acid uptake, and oxidation in CD4 + T RM cells from CD patients . Targeting FAO of CD4 + T RM cells reversed their apoptosis-resistant and proinflammatory phenotype in CD patients. Conclusions CD4 + T RM cells process an accelerated FAO mediated by activated nuclear factor kappa B 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.