RAGE-mediated T cell metabolic reprogramming shapes T cell inflammatory response after stroke

The metabolic reprogramming of peripheral CD4⁺ T cells that occurs after stroke can lead to imbalanced differentiation of CD4⁺ T cells, including regulation of T cells, and presents a promising target for poststroke immunotherapy. However, the regulatory mechanism underlying the metabolic reprogramming of peripheral CD4⁺ T cell remains unknown. In this study, using combined transcription and metabolomics analyses, flow cytometry, and conditional knockout mice, we demonstrate that the receptor for advanced glycation end products (RAGE) can relay the ischemic signal to CD4⁺ T cells, which underwent acetyl coenzyme A carboxylase 1(ACC1)-dependent metabolic reprogramming after stroke. Furthermore, by administering soluble RAGE (sRAGE) after stroke, we demonstrate that neutralization of RAGE reversed the enhanced fatty acid synthesis of CD4⁺ T cells and the post-stroke imbalance of Treg/Th17. Finally, we found that post-stroke sRAGE treatment protected against infarct volume and ameliorated functional recovery. In conclusion, sRAGE can serve as a novel immunometabolic modulator that ameliorates ischemic stroke recovery by inhibiting fatty acid synthesis and thus favoring CD4⁺ T cells polarization toward Treg after cerebral ischemia injury. The above findings provide new insights for the treatment of neuroinflammatory responses after ischemia stroke.