Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol.
Extracellular microvesicles promote microglia-mediated pro-inflammatory responses to ethanol.
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DOI：
10.1002/jnr.24813
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发表时间：
2021-08
影响因子：
4.2
通讯作者：
Coleman LG Jr
中科院分区：
文献类型：
--
作者：
Crews FT;Zou J;Coleman LG Jr
酒精使用障碍(AUD)的病理特征是促炎基因诱导和小胶质细胞激活。促进这种激活的潜在细胞过程仍不清楚。细胞外小泡(EVS)以前被认为是细胞碎片，在几种疾病状态下已成为炎症信号的介质。我们利用原代器官型脑片培养(OBSC)研究了微囊(MVS，直径50 nm-100µm的EVS)在促炎和小胶质功能基因表达中的作用。乙醇引起一种独特的免疫基因特征：促炎症因子α和IL-1β的瞬时诱导，稳态小胶质细胞状态基因TMem119的减少，嘌呤能受体P2RY12和小胶质细胞抑制性分裂因子受体CX3CR1的进行性增加，小胶质细胞突触前基因C1q的增加，吞噬细胞基因TREM2的减少。MV信号转导参与了这一反应，因为丙咪嗪减少MV分泌可阻断乙醇诱导的促炎性肿瘤坏死因子-α和IL-1β，而乙醇条件下的MV(EtoH-MV)在幼稚的脑片上再现了乙醇相关的免疫基因特征。乙醇处理前去除小胶质细胞可阻止Etoh-MVS的促炎活性，HMGB1抑制剂甘草酸孵育Etoh-MVS也是如此。乙醇通过激活PI3激酶诱导MVS培养的BV2小胶质细胞分泌HMGB1。综上所述，这些研究发现，MVS调节与酒精相关的促炎基因诱导和小胶质细胞激活变化。因此，MVS可能代表着一个新的治疗靶点，以减少酒精滥用或其他以神经免疫成分为特征的疾病的神经炎症。[更正于2021年4月5日，首次在线发布后：更改了版权线。]乙醇导致脑组织分泌促炎微囊(MVS)。乙醇诱导的MVS复制了乙醇单独诱导的促炎基因诱导和小胶质细胞激活，抑制它们的分泌可以阻断乙醇诱导的神经炎症。小胶质细胞是产生促炎MVS所必需的，MV的分泌涉及小胶质细胞PI3K的激活。
Alcohol use disorder (AUD) pathology features pro‐inflammatory gene induction and microglial activation. The underlying cellular processes that promote this activation remain unclear. Previously considered cellular debris, extracellular vesicles (EVs) have emerged as mediators of inflammatory signaling in several disease states. We investigated the role of microvesicles (MVs, 50 nm–100 µm diameter EVs) in pro‐inflammatory and microglial functional gene expression using primary organotypic brain slice culture (OBSC). Ethanol caused a unique immune gene signature that featured: temporal induction of pro‐inflammatory TNF‐α and IL‐1β, reduction of homeostatic microglia state gene Tmem119, progressive increases in purinergic receptor P2RY12 and the microglial inhibitory fractalkine receptor CX3CR1, an increase in the microglial presynaptic gene C1q, and a reduction in the phagocytic gene TREM2. MV signaling was implicated in this response as reduction of MV secretion by imipramine blocked pro‐inflammatory TNF‐α and IL‐1β induction by ethanol, and ethanol‐conditioned MVs (EtOH‐MVs) reproduced the ethanol‐associated immune gene signature in naïve OBSC slices. Depletion of microglia prior to ethanol treatment prevented pro‐inflammatory activity of EtOH‐MVs, as did incubation of EtOH‐MVs with the HMGB1 inhibitor glycyrrhizin. Ethanol caused HMGB1 secretion from cultured BV2 microglia in MVs through activation of PI3 kinase. In summary, these studies find MVs modulate pro‐inflammatory gene induction and microglial activation changes associated with ethanol. Thus, MVs may represent a novel therapeutic target to reduce neuroinflammation in the setting of alcohol abuse or other diseases that feature a neuroimmune component. [Correction added on 5 April 2021, after first online publication: The copyright line was changed.] Ethanol causes the secretion of pro‐inflammatory microvesicles (MVs) from brain tissue. Ethanol‐induced MVs reproduce the pro‐inflammatory gene induction and microglial activation seen with ethanol alone, and inhibition of their secretion blocks ethanol‐induced neuroinflammation. Microglia are required for the generation of pro‐inflammatory MVs, with MV secretion involving activation of microglial PI3K.
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影响因子：
25
作者：
Galatro, Thais F.;Holtman, Inge R.;Eggen, Bart J. L.
通讯作者：
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影响因子：
10.6
作者：
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通讯作者：
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影响因子：
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