FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

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) has anti-inflammatory properties by modulating microglia and macrophages, but 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 transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. 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 pro-inflammatory 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 through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, 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 anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

Microglial/Macrophage polarization and function in brain injury and repair after stroke

“…Peroxisome proliferator‐activated receptor gamma (PPARγ) belongs to a superfamily of nuclear receptors that contribute to antioxidant and anti‐inflammatory responses 46 . PPARγ agonists such as rosiglitazone 47 or PPARγ activating factors, such as 1, 25‐dihydroxyvitamin D3 (1, 25‐D3), recombinant human fibroblast growth factor 21 (rhFGF21), and oleic acid 48‐50 attenuate brain inflammation and protect against ischemic injury in murine models of stroke. Specifically, microglia respond with a decrease in M1 phenotypic markers and a parallel increase in M2 markers after PPARγ activation.…”

FGF21 alleviates endothelial mitochondrial damage and prevents BBB from disruption after intracranial hemorrhage through a mechanism involving SIRT6

“…These studies have demonstrated crosstalk between FGF21 and the nervous system. In turn, during some harmful events related to the nervous system, such as TBI, I/R injury, cognitive impairment and neurodegenerative diseases (Chen et al 2018 ; Wang et al 2018b ; Kang et al 2020 ; Jiang et al 2019 ; Wang et al 2020 ), FGF21 can also exert certain protective effects. Nevertheless, whether FGF21 has certain protective effects in ICH injury has yet to be elucidated.…”

Blood-brain barrier dysfunction in ischemic stroke and diabetes: the underlying link, mechanisms and future possible therapeutic targets

“…Human fibroblast growth factor 21 (FGF21) is an endocrine member of fibroblast growth factor family that plays important role in glucose metabolism, lipid metabolism and energy balance [77][78][79]. Previous study demonstrated that the anti-inflammatory effect of recombinant FGF21 on transient focal cerebral ischemia and reperfusion occurs through regulation of microglia and peripheral macrophages via NF-κB and PPARγ signaling pathway [80]. Moreover, recombinant FGF21 has been showed protective effects on acute BBB damage following diabetic stroke through increasing PPARγ activity and upregulation of BBB junctional complex proteins [81].…”