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 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. Editor's summary: Multiple sclerosis (MS) is a demyelinating disease associated with sustained brain inflammation and widespread neuronal degeneration. Li et al. showed that activation of formyl peptide receptor 1 (FPR1) expressed in microglia and brain-infiltrating macrophages triggered an immune response to myelin and promoted microgliosis and neuronal damage in an animal model of MS. Moreover, the authors found that FPR1 was expressed prominently in microglia and macrophages from active human MS lesions, and FPR1 ligands were detected at increased levels in the serum of MS patients at the time of active disease. These results suggest a potential therapeutic target for treating MS. —Mattia Maroso INTRODUCTION: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS). The initiation and progression of MS are believed to be coordinated sequentially in the periphery and CNS, resulting in fluctuating neuroinflammation and persistent neurodegeneration. Although current disease-modifying therapies can suppress the emergence of new brain lesions and the frequency of disease relapses, the benefit of these medications against compartmentalized brain inflammation and degeneration is limited, resulting in unabated disease progression. Thus, there is an unmet and urgent need to identify factors perpetuating CNS inflammation and degeneration, with the potential to develop new therapies to halt MS progression. RATIONALE: Brain lesions in active MS are distinguished by the presence of reactive microgliosis. Reactive microglia, together with macrophages derived from the circulation, coordinate the development of tissue-restricted inflammation during MS progression. Persistent innate immune responses precipitate progressive tissue insults and exacerbate neurodegeneration. During the chronic stage of MS, dying cells in the CNS release danger-associated molecular patterns that are recognized by pattern recognition receptors such as formyl peptide receptor 1 (FPR1), a G protein–coupled receptor preferentially expressed in microglia and macrophages. Engagement of FPR1 by formyl peptides elicits robust innate immune responses, which exacerbate neuronal damage. Furthermore, the endogenous agonist of FPR1, mitochondrial formyl peptide (mtFP), is released by damaged mitochondria, a hallmark of neurodegeneration. RESULTS: We found that FPR1 is prominently expressed in both CNS-resident microglia and CNS-infiltrating, monocyte-derived macrophages within active demyelinating lesions of individuals with MS. Parallel analyses revealed that circulating levels of endogenous N-formylated peptides released from damaged mitochondria dynamically correlate with progressive disease stages of individuals with MS. In experimental mouse models of MS, we demonstrated that FPR1 engagement initiates a protein kinase C (PKC)–dependent signaling cascade, triggering sustained release of reactive oxygen species (ROS) and inflammatory cytokines such as tumor necrosis factor–α (TNF-α) from reactive microglia and macrophages. The ensuing oxidative and inflammatory milieu impaired neural axons, leading to progressive axonal disintegration. Concurrently, FPR1-expressing microglia secreted the C-C motif chemokine ligand 5 (CCL5) to establish an inflammatory microenvironment, facilitating recruitment and clonal expansion of CNS-infiltrating, myelin-reactive CD4+ T cells. These T cells released interferon-γ (IFN-γ), establishing a feedforward loop amplifying myelin sheath destruction by FPR1-expressing microglia and perpetuating neuroinflammation. To explore the therapeutic potential of targeting FPR1 in MS, we used a CNS-penetrating small molecule antagonist of FPR1, T0080, which mitigated autoimmune reactions in the periphery as well as in the CNS and blunted microglia-orchestrated axonal degeneration. CONCLUSION: Our findings unveil FPR1 signaling in sustaining neuroinflammation that exacerbates neurodegeneration in MS and its mouse models. This mechanism-driven discovery of FPR1 and its antagonist T0080 holds promise for slowing MS progression. FPR1 and its antagonist T0080 in MS.: The left hemisphere depicts an MS brain where FPR1 signaling sustains compartmentalized immune reactivity, compromising myelin integrity. The right hemisphere shows an atrophic brain of progressive MS as a result of FPR1-mediated neurodegeneration. The time course of neuroinflammation, neurodegeneration, and the site of action of FPR1 blockade by T0080 are also depicted. MHC II, major histocompatibility complex II. [Figure created with BioRender.com] [ABSTRACT FROM AUTHOR]