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) 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 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 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 proliferator-activated 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 anti-inflammatory agent for stroke treatment.

RETRACTED ARTICLE: Mesenchymal stem cell-derived exosome miR-542-3p suppresses inflammation and prevents cerebral infarction

“…Other studies have confirmed that miR-181a inhibitor treatment can significantly reduce the area of cerebral infarction, reduce the loss of neurological function, reduce the activation of NF-κB, reduce leukocyte infiltration, and protect against cerebral ischemic injury for a long time [ 42 ]. To explore the mechanism of ischemic injury of the brain, we constructed the mouse MCAO model, which is a commonly used animal model to detect cerebral ischemic diseases [ 43 ]. And FJC staining, TTC staining, and neurological grading scores were used to confirm the success of the MCAO model.…”

Fenofibrate Protects against Retinal Dysfunction in a Murine Model of Common Carotid Artery Occlusion-Induced Ocular Ischemia

“…Finally, long-acting FGF21 reduced retinal vascular leakage in a murine model and in human cells by maintaining claudin-1 expression [ 47 ]. In the central nervous system (especially, the brain), recombinant human FGF21 improved ischemic outcomes in a murine model of stroke via alleviation of neuroinflammation [ 48 ]. Delayed recanalization after middle cerebral artery occlusion improved neurological deficits in rats via increasing endogenous FGF21 expression, followed by attenuation of neuronal death in penumbra [ 49 ].…”

Roles of Fibroblast Growth Factors and Their Therapeutic Potential in Treatment of Ischemic Stroke

“…Furthermore, FGF21 decreases the expression of ER stress-related proteins in MCAO rats and PC12 cells (Yang et al, 2018). In addition, in our recent study, we discovered that rhFGF21 treatment alleviates motor nerve dysfunction by modulating microglia/macrophage-mediated neuroinflammation via inhibition of NF-κB signaling pathways (Wang et al, 2020). Overall, FGF21 protects against stroke through actions affecting multiple targets, including promotion of neuronal survival and induction of ER stress and microglia/macrophage-mediated neuroinflammation reductions (Figure 1).…”

“…Ischemic stroke induces the activation of astrocytes and microglia, the production of proinflammatory cytokines and chemokines and further exacerbation of tissue damage. Therefore, suppression of proinflammatory cytokine expression or promotion of antiinflammatory cytokine expression by microglial regulation may be another promising treatment for ischemic stroke (Wang et al, 2020).…”