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Targeting formyl peptide receptor 1 reduces brain inflammation and neurodegeneration
Yulin Li1,2, Zhiguo Li1, Pei Zheng2
1Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China.
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.
Insights
Formyl peptide receptor 1 (FPR1) signaling drives multiple sclerosis (MS) progression by harming microglia and promoting T cell expansion. Antagonizing FPR1 may offer a new therapeutic strategy for MS.
Area of Science:
- Neuroimmunology
- Neuroinflammation
- Molecular mechanisms of neurodegeneration
Background:
- Multiple sclerosis (MS) involves complex neuroinflammation and degeneration.
- The precise mechanisms driving MS progression remain incompletely understood.
Purpose of the Study:
- To investigate the role of formyl peptide receptor 1 (FPR1) in MS pathogenesis.
- To explore FPR1 signaling as a potential therapeutic target for MS.
Main Methods:
- Assessed FPR1 expression in microglia and macrophages from MS patients.
- Correlated blood N-formylated peptide levels with MS disease progression.
- Utilized MS mouse models to study FPR1 signaling effects on microglial function and axonal integrity.
- Administered a small molecule FPR1 antagonist (T0080) in MS models.
Main Results:
- Elevated FPR1 expression was observed in CNS immune cells of MS patients.
- Increased FPR1 signaling in microglia led to mitochondrial dysfunction, axonal loss, and apoptosis in MS models.
- FPR1-expressing microglia promoted the expansion of myelin-reactive CD4+ T cells.
- FPR1 antagonism with T0080 reduced autoimmune responses and axonal damage.
Conclusions:
- FPR1 signaling represents a key mechanism contributing to MS progression.
- Targeting FPR1 with antagonists presents a promising therapeutic avenue for managing MS.
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