Sodium butyrate triggers a functional elongation of microglial process via Akt-small RhoGTPase activation and HDACs inhibition
Sodium butyrate triggers a functional elongation of microglial process via Akt-small RhoGTPase activation and HDACs inhibition
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DOI：
10.1016/j.nbd.2017.12.006
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发表时间：
2018-03
影响因子：
6.1
通讯作者：
Peng Wang;Yaru Zhang;Yu Gong;Rongrong Yang;Zhuo Chen;Wenfeng Hu;Yue Wu;Minhui Gao;Xing Xu;Yibin Qin;Chao Huang
中科院分区：
文献类型：
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作者：
Peng Wang;Yaru Zhang;Yu Gong;Rongrong Yang;Zhuo Chen;Wenfeng Hu;Yue Wu;Minhui Gao;Xing Xu;Yibin Qin;Chao Huang
小胶质细胞是大脑中的一种免疫细胞，在正常情况下处于分支状态，具有分支过程。在病理刺激下，小胶质细胞收缩它们的突起并被激活。寻找使活化的小胶质细胞恢复到分枝状态的方法将有助于科普神经炎症引起的损伤。在这里，我们研究了丁酸钠（SB）的影响，丁酸钠盐的形式产生的发酵的膳食纤维在肠道小胶质细胞的过程。结果表明，SB在正常和炎症条件下均能诱导小胶质细胞突起可逆性延长，并伴随着反映小胶质细胞促炎和抗炎状态的标志物的显著变化。蛋白激酶B（Akt）-RhoGTP酶信号被认为介导SB对小胶质细胞过程的作用，因为：i）SB激活小RhoGTP酶Rac 1和Cdc 42; ii）SB促进Akt磷酸化; iii）Rac 1、Cdc 42和Akt抑制消除SB对小胶质细胞过程的促延伸作用。进一步的分析表明，与另外两种组蛋白脱乙酰酶（HDAC）抑制剂阿司他丁A（TSA）和丙戊酸（VPA）孵育的小胶质细胞也促进了小胶质细胞突起的伸长和Akt磷酸化，这表明SB触发的小胶质细胞突起的伸长可能是由HDAC抑制介导的。此外，Akt抑制阻止SB在原代培养的小胶质细胞中的抗炎作用，并取消SB对脂多糖（LPS）诱导的小胶质细胞突起收缩和行为异常的抑制作用。这些结果第一次从小胶质细胞突起延长的角度确定了SB的抗炎作用。
Microglia, a type of immune cell in the brain, are in a ramified status with branched processes in normal conditions. Upon pathological stimulation, microglia retract their processes and become activated. Searching methods to make the activated microglia return to ramified status would help cope with injuries induced by neuroinflammation. Here, we investigated the influence of sodium butyrate (SB), a sodium salt form of butyrate produced by fermentation of dietary fibers in the gut on microglial process. Results showed that SB induced reversible elongations of microglial process in both normal and inflammatory conditions, and these elongations were accompanied with significant changes in markers reflecting the pro-inflammatory and anti-inflammatory status of microglia. The protein kinase B (Akt)-RhoGTPase signal was considered to mediate the effect of SB on microglial process, as: i) SB activated the small RhoGTPases Rac1 and Cdc42; ii) SB promotes Akt phosphorylation; iii) Rac1, Cdc42, and Akt inhibition abrogated the pro-elongation effect of SB on microglial process. Further analysis showed that incubation of microglia with two other histone deacetylases (HDACs) inhibitors trichostatin A (TSA) and valproic acid (VPA) also promoted microglial process elongation and Akt phosphorylation, suggesting that the SB-triggered microglial process elongation may be mediated by HDACs inhibition. Furthermore, Akt inhibition prevented the anti-inflammatory effect of SB in primary cultured microglia, and abrogated the inhibitory effects of SB on microglial process retraction and behavioral abnormalities induced by lipopolysaccharide (LPS). These results for the first time identify an anti-inflammatory role of SB from the aspect of microglial process elongation.