Yulin Li, Yulin Li, Zhiguo Li, Pei Zheng, Shuzhen Guan, Yan Li, Yan Li, Nan Yao, Zhihui Qi, X. Zhang, Lei Su, Jing Jing, Siting Wu, Xue Zhao, Meng Wang, Chotima Böttcher, Hans‐Gustaf Ljunggren, Friedemann Paul, Luc Van Kaer, Alexei Verkhratsky, Fu‐Dong Shi
Multiple sclerosis (MS) progresses through brain region–specific inflammation and degeneration, with poorly defined mechanisms. In individuals with MS, we identified increased expression of formyl peptide receptor 1 (FPR1) in central nervous system (CNS)–resident microglia and CNS-infiltrating macrophages. Blood amounts of N -formylated peptides, which are endogenous agonists of FPR1, correlated with disease progression in patients with MS. In MS mouse models, signaling through FPR1 promoted microglial mitochondrial dysfunction, causing axonal loss and apoptosis. FPR1-expressing microglia sustained the clonal expansion of myelin-reactive CD4 + T cells in the CNS. A CNS-penetrating small molecule FPR1 antagonist, T0080, mitigated autoimmune responses and axonal degeneration. Our study identifies FPR1 signaling as a potential mechanism for MS progression and suggests antagonizing FPR1 as a therapeutic approach.