Ecto-5'-nucleotidase (CD73) attenuates inflammation after spinal cord injury by promoting macrophages/microglia M2 polarization in mice.
Ecto-5'-nucleotidase (CD73) attenuates inflammation after spinal cord injury by promoting macrophages/microglia M2 polarization in mice.
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DOI：
10.1186/s12974-018-1183-8
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发表时间：
2018-05-22
影响因子：
9.3
通讯作者：
Lu F
中科院分区：
文献类型：
--
作者：
Xu S;Zhu W;Shao M;Zhang F;Guo J;Xu H;Jiang J;Ma X;Xia X;Zhi X;Zhou P;Lu F
免疫激活，特别是巨噬细胞和常驻小胶质细胞的激活，导致炎症，是脊髓损伤(SCI)进展的关键组成部分。巨噬细胞/小胶质细胞以两种状态存在--经典激活的M1表型具有促炎作用，或者交替激活的M2表型具有抗炎作用。胞外-5‘-核苷酸酶(CD73)是一种免疫抑制分子，参与适应性和先天免疫反应，能够将AMP脱磷为腺苷。然而，目前尚不清楚CD73是否能够调节巨噬细胞/小胶质细胞在M1和M2表型之间的转化。我们使用基因缺陷小鼠来确定CD73在体内脊髓损伤后巨噬细胞/小胶质细胞极化中的作用。我们使用小干扰RNA(SiRNA)或pcDNA3.1在BV2细胞中抑制或过表达CD73，以验证在体外的前发现。采用分子和组织学相结合的方法检测巨噬细胞/小胶质细胞极化，并探讨其在体内和体外的作用机制。我们发现脊髓损伤后CD73表达上调。与同样造成脊髓损伤的野生型小鼠相比，CD73缺陷小鼠表现出压倒性的免疫反应，较少的抗炎表型巨噬细胞/小胶质细胞，运动恢复较差。体外研究发现，CD73的抑制抑制了BV2细胞特有的小胶质细胞抗炎极化标志物的表达，而CD73的过度表达则相反。随后的实验证实，CD73通过刺激p38MAPK促进小胶质细胞的选择性激活。我们可以得出结论，CD73通过介导巨噬细胞/小胶质细胞极化而发挥神经保护作用。这些发现有助于更好地了解触发巨噬细胞/小胶质细胞表型变化的调节因子，从而揭示可能成为创新脊髓损伤治疗目标的额外分子和途径。本文的在线版本(10.1186/s12974-0181183-8)包含向授权用户提供的补充材料。
Immune activation, specifically activation of macrophages and resident microglia, leading to inflammation is a key component in the progression of spinal cord injury (SCI). Macrophages/microglia exist in two states—the classically activated M1 phenotype that confers pro-inflammatory effects or the alternatively activated M2 phenotype that confers anti-inflammatory effects. Ecto-5′-nucleotidase (CD73) is an immunosuppressive molecule intricately involved in adaptive and innate immune responses and is able to dephosphorylate AMP to adenosine. However, it is not known if CD73 is able to modulate the macrophages/microglia transformation between the M1 and M2 phenotypes. We used gene-deficient mice to determine the role of CD73 in macrophages/microglia polarization post-SCI in vivo. We used small interference RNA (siRNA) or pcDNA3.1 to inhibit or overexpress CD73 in BV2 cells to verify anterior discovery in vitro. A combination of molecular and histological methods was used to detect the macrophages/microglia polarization and explore the mechanism both in vivo and in vitro. We found that SCI induced the upregulation of CD73 expression. CD73 deficient mice were noted to demonstrate overwhelming immune responses, few anti-inflammatory phenotype macrophages/microglia, and had a poorer locomotor recovery in comparison to wild-type mice that were also inflicted with SCI. In vitro studies found that CD73 suppression inhibited the expression of characteristic microglial anti-inflammatory polarization markers in BV2 cells, while the converse was noted in CD73 overexpression. Subsequent experiments confirmed that CD73 promoted microglia alternative activation by stimulating p38 MAPK. We were able to conclude that CD73 imparts neuroprotective effects by mediating macrophages/microglia polarization. These findings allow for better understanding of the modulatory factors involved in triggering the change in macrophages/microglia phenotypes, therefore uncovering additional molecules and pathways that may be targeted in the innovation of novel SCI therapies. The online version of this article (10.1186/s12974-018-1183-8) contains supplementary material, which is available to authorized users.
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影响因子：
13.6
作者：
Antonioli L;Pacher P;Vizi ES;Haskó G
通讯作者：
Haskó G
影响因子：
9.3
作者：
Cherry JD;Olschowka JA;O'Banion MK
通讯作者：
O'Banion MK
影响因子：
--
作者：
Gao ZW;Dong K;Zhang HZ
通讯作者：
Zhang HZ
影响因子：
2.9
作者：
Braun, N;Lenz, C;Zimmermann, H
通讯作者：
Zimmermann, H
DOI：
10.1523/jneurosci.3257-09.2009
发表时间：
2009-10-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kigerl KA;Gensel JC;Ankeny DP;Alexander JK;Donnelly DJ;Popovich PG
通讯作者：
Popovich PG