FGF21 Protects the Blood-Brain Barrier by Upregulating PPARγ via FGFR1/β-Klotho Following Traumatic Brain Injury.

Blood-brain barrier (BBB) disruption and dysfunction result in brain edema, which is responsible for more than half of all deaths after severe traumatic brain injury (TBI). Fibroblast growth factor 21 (FGF21) has a potential neuroprotective function in the brain. However, the effects and underlying possible mechanism of action on BBB integrity following TBI remain unknown. The purpose of the current study was to determine the effects of FGF21 on BBB protection and TBI treatment. The effects of recombinant human FGF21 (rhFGF21) on BBB integrity and on tight junction (TJ) and adhesion junction (AJ) proteins were investigated both in a TBI mouse model and an in vitro BBB disruption model established with tumor necrosis factor alpha (TNF-alpha)-induced human brain microvascular endothelial cells (HBMECs). The ability of rhFGF21 to form an FGF21/FGFR1/beta-klotho complex was confirmed by in vitro beta-klotho small interfering RNA (siRNA) transfection and FGFR1 co-immunoprecipitation. In addition, the specific FGFR1 and peroxisome proliferator-activated receptor gamma (PPAR gamma) inhibitors PD173074 and GW9662, respectively, were applied to further explore the possible mechanism of rhFGF21 in BBB maintenance after TBI. rhFGF21 markedly reduced neurofunctional behavior deficits and cerebral edema degree, preserved BBB integrity, and recued brain tissue loss and neuron apoptosis in the mouse model after TBI. Both in vivo and in vitro, rhFGF21 upregulated TJ and AJ proteins, thereby preserving the BBB. Moreover, rhFGF21 activated PPAR gamma in TNF-alpha-induced HBMECs through formation of an FGF21/FGFR1/beta-klotho complex. rhFGF21 protected the BBB through FGF21/FGFR1/beta-klotho complex formation and PPAR gamma activation, which upregulated TJ and AJ proteins.