Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration

• 成果类型: Article
• 署名作者: Li, Yulin; Li, Zhiguo; Zheng, Pei; Guan, Shuzhen; Li, Yan; Yao, Nan; Qi, Zhihui; Zhang, Xueyu; Su, Lei; Jing, Jing; Wu, Siting; Zhao, Xue; Wang, Meng; Bottcher, Chotima; Ljunggren, Hans-Gustaf; Paul, Friedemann; Van Kaer, Luc; Verkhratsky, Alexei; Shi, Fu-Dong
• 署名单位: Tianjin Medical University; Capital Medical University; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Karolinska Institutet; Karolinska University Hospital; Vanderbilt University; University of Manchester
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adq1177
• 发表日期: 2025-11-13
• 页码: eadq1177
• 关键词: multiple-sclerosis; mouse model; activation; neutrophils; microglia; cells; protein; shape

摘要

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.