2. Academic Validation
  3. Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration

Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration

  • Science. 2025 Nov 13;390(6774):eadq1177. doi: 10.1126/science.adq1177.
Yulin Li # 1 2,  Zhiguo Li # 1,  Pei Zheng 2,  Shuzhen Guan 1 2,  Yan Li 2,  Nan Yao 1,  Zhihui Qi 1,  Xueyu Zhang 1,  Lei Su 1,  Jing Jing 2,  Siting Wu 1,  Xue Zhao 1,  Meng Wang 3,  Chotima Böttcher 3,  Hans-Gustaf Ljunggren 4,  Friedemann Paul 3,  Luc Van Kaer 5,  Alexei Verkhratsky 6,  Fu-Dong Shi 1 2
Affiliations

Affiliations

  • 1 Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
  • 2 Department of Neurology, Tiantan Neuroimaging Center of Excellence, China National Clinical Research Canter for Neurological Disease, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
  • 3 Experimental and Clinical Research Center, Charité - Universitätsmedizin Berlin and Max Delbrueck Center for Molecular Medine, Berlin, Germany.
  • 4 Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
  • 5 Department of Pathology, Microbiology, and Immunology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 6 Faculty of Biology, Medicine and Health, the University of Manchester, Manchester, UK.
  • # Contributed equally.
PMID: 41231983 DOI: 10.1126/science.adq1177
Abstract

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.

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