FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microgli
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(2020) 17:257
RESEARCH
Open Access
FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages Wang Dongxue1,2, Liu Fei2, Zhu Liyun2, Lin Ping2, Han Fanyi2, Wang Xue2, Tan Xianxi1, Lin Li1,2* and Xiong Ye1*
Abstract Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of proinflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferatoractivated receptor-γ (PPAR-γ). Conclusions: rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/ macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential antiinflammatory agent for stroke treatment. Keywords: rhFGF21, Stroke, Neuroinflammation, Microglia/macrophage, NF-κB, PPAR-γ
* Correspondence: [email protected]; [email protected] 1 Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, Zhejiang, China Full list of author information is available at the end of the article © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, dist
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