Division of Preclinical Innovation, National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, Rockville, MD, USA.
Laboratory of Immune System Biology, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA.
Sci Rep. 2020 Feb 28;10(1):3766. doi: 10.1038/s41598-020-60610-5.
Th17 cells are critical drivers of autoimmune diseases and immunopathology. There is an unmet need to develop therapies targeting pathogenic Th17 cells for the treatment of autoimmune disorders. Here, we report that anxiolytic FGIN-1-27 inhibits differentiation and pathogenicity of Th17 cells in vitro and in vivo using the experimental autoimmune encephalomyelitis (EAE) model of Th17 cell-driven pathology. Remarkably, we found that the effects of FGIN-1-27 were independent of translocator protein (TSPO), the reported target for this small molecule, and instead were driven by a metabolic switch in Th17 cells that led to the induction of the amino acid starvation response and altered cellular fatty acid composition. Our findings suggest that the small molecule FGIN-1-27 can be re-purposed to relieve autoimmunity by metabolic reprogramming of pathogenic Th17 cells.
Th17 细胞是自身免疫性疾病和免疫病理学的关键驱动因素。目前迫切需要开发针对致病性 Th17 细胞的治疗方法，以治疗自身免疫性疾病。在这里，我们报告了一种抗焦虑药 FGIN-1-27，它可以通过实验性自身免疫性脑脊髓炎 (EAE) 模型中的 Th17 细胞驱动的病理学，在体外和体内抑制 Th17 细胞的分化和致病性。值得注意的是，我们发现 FGIN-1-27 的作用不依赖于转位蛋白（TSPO），即该小分子的报告靶点，而是由 Th17 细胞中的代谢转换驱动，导致诱导氨基酸饥饿反应和改变细胞脂肪酸组成。我们的研究结果表明，小分子 FGIN-1-27 可以通过对致病性 Th17 细胞的代谢重编程来重新用于缓解自身免疫。
