Targeting formyl peptide receptor 2 to suppress neuroinflammation in neuromyelitis optica spectrum disorder

<b>Background:</b> Neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated neurological inflammatory disease. As a G protein-coupled receptor, formyl peptide receptor 2 (FPR2) orchestrates innate and adaptive immunity. Yet the precise role of FPR2 in neuroinflammation is poorly understood. <b>Methods:</b> Peripheral blood samples were collected from patients with NMOSD and healthy controls. Single-cell RNA sequencing (scRNA-seq) and flow cytometry were employed to assess the expression of FPR2 in immune cell subsets. We used a mouse model of NMOSD to examine the therapeutic potential and underlying immune mechanisms of an FPR2 antagonist Quin-C7. MRI and immunostaining were performed to quantify central nervous system injury. <b>Results:</b> ScRNA-seq and flow cytometry analyses revealed that FPR2 was expressed in various myeloid and lymphoid cell types in patients with NMOSD and a mouse model of NMOSD. In NMOSD mice, mouse formyl peptide receptor 2 (mFpr2) was mainly upregulated in microglia. Administration of Quin-C7 led to reduced brain lesion volume, astrocyte loss and demyelination in NMOSD mice. Further, FPR2 antagonism reduced the inflammatory activity of microglia and lymphocyte infiltration into the brain. Notably, depletion of microglia using a CSF1R inhibitor diminished the protective effects of FPR2 antagonism, suggesting that microglia contribute to the benefit of FPR2 antagonism in NMOSD. In contrast, genetic deficiency of T and B cells or antibody depletion of NK cells did not affect the benefit of FPR2 antagonism. <b>Conclusion:</b> Collectively, our findings revealed a previously unrecognized role of FPR2/mFpr2 in control of microglia activity during neuroinflammation, implying that FPR2 antagonism may serve as a viable therapeutic approach to restrict detrimental neuroinflammation and warrant further investigation.