2. Academic Validation
  3. FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy

FPR2/ALX stimulation modulates microglia and natural killer cells to restrict autoimmune astrocytopathy

  • Acta Pharmacol Sin. 2026 Mar 10. doi: 10.1038/s41401-026-01778-w.
Cai-Yun Qi # 1 2,  Li-Xiang Chen # 2,  Yi-Wei Fu # 2,  Peng-Xu Wang # 3,  Wei Zhang # 1,  Ya-Li Han 2,  Tong-Xiao Xu 2,  Yuan Li 4,  Xiao-Zhen Wang 4,  Gui-Yun Cui 1,  Hao Chen 5,  Ming-Wei Wang 6 7 8 9,  Qiang Liu 10 11
Affiliations

Affiliations

  • 1 Department of Neurology, Parkinson's Disease Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China.
  • 2 Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, International Joint Laboratory of Ocular Diseases, Ministry of Education, Haihe Laboratory of Cell Ecosystem, Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin, 300052, China.
  • 3 The 988th Hospital of PLA Joint Logistics Support Force, Zhengzhou, 450042, China.
  • 4 Research Center for Deepsea Bioresources, Sanya, 572025, China.
  • 5 Department of Neurology, Parkinson's Disease Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China. [email protected].
  • 6 Research Center for Deepsea Bioresources, Sanya, 572025, China. [email protected].
  • 7 Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. [email protected].
  • 8 Research Center for Medicinal Structural Biology, National Research Center for Translational Medicine at Shanghai, State Key Laboratory of Medical Genomics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China. [email protected].
  • 9 Engineering Research Center of Tropical Medicine Innovation and Transformation of Ministry of Education, School of Pharmacy, Hainan Medical University, Haikou, 570228, China. [email protected].
  • 10 Department of Neurology, Parkinson's Disease Center, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221006, China. [email protected].
  • 11 Department of Neurology, Tianjin Neurological Institute, Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, International Joint Laboratory of Ocular Diseases, Ministry of Education, Haihe Laboratory of Cell Ecosystem, Laboratory of Post-Neuroinjury Neurorepair and Regeneration in Central Nervous System Tianjin & Ministry of Education, Tianjin Medical University General Hospital, Tianjin, 300052, China. [email protected].
  • # Contributed equally.
PMID: 41807546 DOI: 10.1038/s41401-026-01778-w
Abstract

Autoantibody- and complement-mediated cytotoxicity can cause autoimmune astrocytopathy that leads to CNS inflammatory demyelination. Formyl peptide receptor 2 (FPR2/ALX) governs the activation and propagation of immune response. However, the precise role of FPR2/ALX in neuroinflammation and the effect of FPR2/ALX stimulation on autoimmune astrocytopathy are poorly understood. Using a mouse model of autoimmune astrocytopathy induced by AQP4-IgG- and complement-mediated cytotoxicity, we found that the stimulation of FPR2/ALX with the small-molecule agonist Quin-C1 led to reduced brain lesion volume, astrocyte loss and demyelination. This was accompanied by enhanced anti-inflammatory activity of microglia and reduced infiltration of lymphocytes in the brain. FPR2/ALX stimulation also led to increased phosphorylation of Syk and Akt in mice with autoimmune astrocytopathy. Notably, the benefits of FPR2/ALX stimulation were attenuated in mice with autoimmune astrocytopathy after microglial depletion using the CSF1R inhibitor PLX5622 or natural killer (NK) cell depletion using an anti-NK1.1 monoclonal antibody. Additionally, the protective effects of FPR2/ALX stimulation were diminished in mice with autoimmune astrocytopathy that received the Syk Inhibitor R406. Collectively, our findings demonstrate that FPR2/ALX stimulation may represent a promising therapeutic strategy to attenuate detrimental neuroinflammation in autoimmune astrocytopathy by modulating microglia and NK cells. FPR2/ALX stimulation suppresses autoimmune astrocytopathy: Using a mouse model of autoimmune astrocytopathy, we demonstrated that FPR2/ALX stimulation with the small molecule Quin-C1 reduces the CNS infiltration of lymphocytes and augments the anti-inflammatory activity of microglia, leading to attenuated astrocyte pathology induced by AQP4-IgG and complement-mediated attacks. Mechanistically, the benefits of FPR2/ALX stimulation using Quin-C1 involve microglia, natural killer (NK) cells, and SYK-AKT signaling.

Keywords

FPR2/ALX; Quin-C1; SYK-AKT pathway; autoimmune astrocytopathy; microglia.

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