Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration
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 <i>N</i>-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<sup>+</sup> 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.
Authors
- Zhihui Qi (ORCID: https://orcid.org/0000-0002-7546-0875)
- Chotima Böttcher (ORCID: https://orcid.org/0000-0002-6226-586X)
- Shuzhen Guan (ORCID: https://orcid.org/0000-0002-6915-4142)
- Lei Su (ORCID: https://orcid.org/0000-0002-5569-1991)
- Friedemann Paul (ORCID: https://orcid.org/0000-0002-6378-0070)
- Nan Yao
- Siting Wu
- Alexei Verkhratsky (ORCID: https://orcid.org/0000-0003-2592-9898)
- Luc Van Kaer (ORCID: https://orcid.org/0000-0001-5275-2309)
- X. Zhang (ORCID: https://orcid.org/0009-0002-4585-6315)
- Hans‐Gustaf Ljunggren (ORCID: https://orcid.org/0000-0003-0908-7387)
- Meng Wang (ORCID: https://orcid.org/0000-0002-0650-2170)
- Zhiguo Li (ORCID: https://orcid.org/0000-0002-6869-2766)
- Xue Zhao (ORCID: https://orcid.org/0000-0003-3111-9648)
- Yan Li (ORCID: https://orcid.org/0000-0003-0815-3565)
- Jing Jing (ORCID: https://orcid.org/0000-0001-9822-5758)
- Fu‐Dong Shi (ORCID: https://orcid.org/0000-0002-9675-4637)
- Pei Zheng (ORCID: https://orcid.org/0000-0002-5170-3123)
- Yulin Li
Institutions
- Karolinska University Hospital (SE)
- Vanderbilt University (US)
- Max Delbrück Center (DE)
- Tianjin Medical University General Hospital (CN)
- Karolinska Institutet (SE)
- University of Manchester (GB)
- Beijing Tian Tan Hospital (CN)
Publication Details
- Journal
- Science
- Published
- 2025-11-13
- DOI
- https://doi.org/10.1126/science.adq1177
- Citations
- 6
- Primary Topic
- S100 Proteins and Annexins
- Type
- article
- Field-Weighted Citation Impact
- 4.84