FGF21 Protects the Blood-Brain Barrier by Upregulating PPARγ via FGFR1/β-klotho after Traumatic Brain Injury
FGF21 Protects the Blood-Brain Barrier by Upregulating PPARγ via FGFR1/β-klotho after Traumatic Brain Injury
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FGF21 在创伤性脑损伤后通过 FGFR1/β-Klotho 上调 PPARγ 来保护血脑屏障
DOI：
10.1089/neu.2017.5271
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发表时间：
2018-09-01
影响因子：
4.2
通讯作者：
Lin, Li
中科院分区：
文献类型：
--
作者：
Chen, Jun;Hu, Jian;Lin, Li
血脑屏障 (BBB) 破坏和功能障碍会导致脑水肿，导致严重创伤性脑损伤 (TBI) 后一半以上的死亡。成纤维细胞生长因子 21 (FGF21) 在大脑中具有潜在的神经保护功能。然而，TBI 后对 BBB 完整性的影响和潜在的可能作用机制仍然未知。本研究的目的是确定 FGF21 对 BBB 保护和 TBI 治疗的影响。在 TBI 小鼠模型和用肿瘤坏死因子 α (TNF-α) 诱导的人脑微血管内皮细胞 (HBMEC) 建立的体外 BBB 破坏模型中研究了重组人 FGF21 (rhFGF21) 对 BBB 完整性以及紧密连接 (TJ) 和粘附连接 (AJ) 蛋白的影响。通过体外 β-klotho 小干扰 RNA (siRNA) 转染和 FGFR1 免疫共沉淀证实了 rhFGF21 形成 FGF21/FGFR1/β-klotho 复合物的能力。此外，分别应用特异性FGFR1和过氧化物酶体增殖物激活受体γ（PPARγ）抑制剂PD173074和GW9662进一步探讨rhFGF21在TBI后BBB维持中的可能机制。 rhFGF21 显着减轻 TBI 后小鼠模型的神经功能行为缺陷和脑水肿程度，保留 BBB 完整性，并恢复脑组织损失和神经元凋亡。在体内和体外，rhFGF21 上调 TJ 和 AJ 蛋白，从而保护 BBB。此外，rhFGF21 通过形成 FGF21/FGFR1/beta-klotho 复合物，在 TNF-α 诱导的 HBMEC 中激活 PPAR gamma。 rhFGF21 通过 FGF21/FGFR1/beta-klotho 复合物形成和 PPAR gamma 激活来保护 BBB，从而上调 TJ 和 AJ 蛋白。
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.