Dexmedetomidine Mitigates Microglia-Mediated Neuroinflammation through Upregulation of Programmed Cell Death Protein 1 in a Rat Spinal Cord Injury Model
Dexmedetomidine Mitigates Microglia-Mediated Neuroinflammation through Upregulation of Programmed Cell Death Protein 1 in a Rat Spinal Cord Injury Model
复制标题
右美托咪定通过上调大鼠脊髓损伤模型中的程序性细胞死亡蛋白 1 减轻小胶质细胞介导的神经炎症
DOI：
10.1089/neu.2017.5625
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发表时间：
2018-06-07
影响因子：
4.2
通讯作者：
Lin, Wenping
中科院分区：
文献类型：
--
作者：
He, Hefan;Zhou, Yingying;Lin, Wenping
过度的神经炎症加重了脊髓损伤(SCI)后的神经损伤。控制神经炎症可能有利于神经再生和组织修复。先前的研究报道右旋美托咪定可抑制脊髓损伤后的神经炎症。在本研究中，为了确定右美托咪定抑制神经炎症的机制，我们在体外和大鼠脊髓损伤模型中测试了盐酸右美托咪定对小胶质细胞的影响。我们发现，盐酸右美托咪定上调了免疫调节分子程序性细胞死亡蛋白1(PD-1)在激活的小胶质细胞中的表达，但不上调静止的小胶质细胞中的表达。在程序性死亡配体1(PD-L1)存在的情况下，促进PD-1的表达，下调促炎细胞因子的表达，并上调激活的小胶质细胞的抗炎细胞因子的表达。PD-L1/PD-1结合也可诱导小胶质细胞向免疫调节型M2分化。此外，盐酸右美托咪定可促进激活的小胶质细胞内5‘-腺苷一磷酸活化蛋白激酶(AMPK)信号转导。AMPK信号通路参与了上述细胞因子表达和M2小胶质细胞极化的改变。在大鼠脊髓损伤模型中，腹腔注射盐酸右美托咪定对小胶质细胞也有类似的影响。综上所述，我们的研究揭示了右旋美托咪定抗神经炎作用的新机制：右旋美托咪定通过上调小胶质细胞PD-1的表达来促进激活的小胶质细胞的AMPK信号转导，从而推动小胶质细胞向M2型极化。
Excessive neuroinflammation aggravates neurological damage after spinal cord injury (SCI). Controlling neuroinflammation might favor neuroregeneration and tissue repair. Dexmedetomidine is reported to inhibit post-SCI neuroinflammation in previous research. In the current study, to determine the mechanisms by which dexmedetomidine inhibits neuroinflammation, we tested the effect of dexmedetomidine hydrochloride on microglia in vitro and in a rat SCI model. We found that dexmedetomidine hydrochloride up-regulated programmed cell death protein 1 (PD-1), an immunoregulatory molecule, in activated microglia but not in resting microglia. In the presence of programmed death-ligand 1 (PD-L1), this enhanced PD-1 expression downregulated pro-inflammatory cytokine expression and upregulated anti-inflammatory cytokine expression in activated microglia. PD-L1/PD-1 engagement also induced microglia polarization toward the immunoregulatory M2 type. Moreover, dexmedetomidine hydrochloride promoted 5' adenosine monophosphate-activated protein kinase (AMPK) signaling in activated microglia. AMPK signaling was responsible for the above-mentioned changes of cytokine expression and M2 microglia polarization. Consistently, intraperitoneal injection of dexmedetomidine hydrochloride had a similar effect on microglia in the rat SCI model. Taken together, our study disclosed a novel mechanism underlying the anti-neuroinflammatory effect of dexmedetomidine: dexmedetomidine promotes AMPK signaling in activated microglia via upregulation of microglial PD-1 expression, and subsequently drives microglia polarization toward M2 type.