FGF20 alleviates neuroinflammation in ischemic stroke by modulating microglial polarization via TREM2-TLR4/NF-κB...

Microglia play dual roles in neuroinflammation, driving either detrimental M1 or protective M2 polarization, which critically impacts the outcomes of ischemic stroke. While fibroblast growth factor 20 (FGF20) is established as a neurotrophic factor with neuroprotective properties, its role in regulating microglial polarization remains unclear. This study investigated a novel function of FGF20 in alleviating post-stroke neuroinflammation and its underlying mechanisms. In a rat model of middle cerebral artery occlusion (MCAO), intracerebroventricular administration of FGF20 significantly reduced infarct volume and improved neurological function. RT-PCR analysis revealed that FGF20 bidirectionally regulated cytokine expression, suppressing M1-associated markers (CD86, IL-1β, IL-6, iNOS, TNF-α) while enhancing M2-associated markers (IL-10, Arg-1). Immunofluorescence staining demonstrated that FGF20 attenuated microglia activation in peri-infarct striatum and hippocampus. In vitro, FGF20 counteracted LPS-induced M1 polarization in primary microglia, downregulated the TLR4/NF-κB pathway, and upregulated TREM2 expression. Notably, while the selective FGFR1 inhibitor PD173074 abolished FGF20-induced TREM2 upregulation, it did not reverse the suppression of TLR4/NF-κB, indicating that these two effects are mediated through distinct regulatory mechanisms. These phenotypic shifts were further confirmed by a reduction in CD32/16⁺ (M1) cells and an increase in Arg1⁺ (M2) cells. Mechanistically, FGF20 restored the balance between TREM2 and TLR4 signaling, inhibiting NF-κB activation and attenuating neuroinflammatory responses. Collectively, our findings identify FGF20 as a novel dual modulator of microglial polarization that integrates TREM2-mediated immunoregulation with FGFR1-dependent and independent suppression of TLR4/NF-κB pathway. Thus, FGF20 represents a promising therapeutic candidate for ischemic stroke, extending its functional profile from neuroprotection to targeted immunomodulation through phenotype-specific regulation of microglial polarization.