Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion
Astrocytes initiate inflammation in the injured mouse spinal cord by promoting the entry of neutrophils and inflammatory monocytes in an IL-1 receptor/MyD88-dependent fashion
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DOI：
10.1016/j.bbi.2009.11.007
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发表时间：
2010-05-01
影响因子：
15.1
通讯作者：
Lacroix, Steve
中科院分区：
文献类型：
--
作者：
Pineau, Isabelle;Sun, Libo;Lacroix, Steve
中枢神经系统损伤可刺激多种致炎细胞因子和趋化因子的表达，其中一些包括MCP-1(又称CCL2)、KC(CXCL1)和MIP-2(CXCL2)在病变部位募集Gr-1(+)白细胞。虽然早期的研究报道了中性粒细胞和单核/巨噬细胞参与了脊髓损伤后继发性组织丢失，但最近的研究表明，Gr-1(+)白细胞的耗竭损害了组织的愈合，并恶化了功能恢复。在这里，我们证明星形胶质细胞在脊髓损伤后3到12小时内迅速合成MCP-1、KC和MIP-2，从而导致早期神经炎症。星形胶质细胞表达趋化因子之后，血液来源的免疫细胞，如I型“炎性”单核细胞和中性粒细胞，渗入病变部位和附近的受损区域。有趣的是，MyD88信号缺陷小鼠的星形胶质细胞产生的MCP-1和MIP-2显著减少，并且无法合成KC。MyD88依赖受体的作用分析表明，MCP-1、KC和MIP-2的星形细胞表达是由IL-1受体(IL-1R1)介导的，而不是TLR2或TLR4。对MyD88和IL-1R1基因敲除小鼠脊髓细胞的流式细胞术分析证实，脊髓损伤后12小时和4天，1型“炎性”单核细胞显著减少，中性粒细胞几乎完全消失。综上所述，这些结果表明MyD88/IL-1R1信号调节中性粒细胞进入脊髓损伤部位，在较小程度上调节I型“炎性”单核细胞进入脊髓损伤部位。(C)2009 Elsevier Inc.保留所有权利。
CNS injury stimulates the expression of several proinflammatory cytokines and chemokines, some of which including MCP-1 (also known as CCL2), KC (CXCL1), and MIP-2 (CXCL2) act to recruit Gr-1(+) leukocytes at lesion sites. While earlier studies have reported that neutrophils and monocytes/macrophages contribute to secondary tissue loss after spinal cord injury (SCI), recent work has shown that depletion of Gr-1(+) leukocytes compromised tissue healing and worsened functional recovery. Here, we demonstrate that astrocytes distributed throughout the spinal cord initially contribute to early neuroinflammation by rapidly synthesizing MCP-1, KC, and MIP-2, from 3 up to 12 h post-SCI. Chemokine expression by astrocytes was followed by the infiltration of blood-derived immune cells, such as type I "inflammatory" monocytes and neutrophils, into the lesion site and nearby damaged areas. Interestingly, astrocytes from mice deficient in MyD88 signaling produced significantly less MCP-1 and MIP-2 and were unable to synthesize KC. Analysis of the contribution of MyD88-dependent receptors revealed that the astrocytic expression of MCP-1, KC, and MIP-2 was mediated by the IL-1 receptor (IL-1R1), and not by TLR2 or TLR4. Flow cytometry analysis of cells recovered from the spinal cord of MyD88- and IL-1R1-knockout mice confirmed the presence of significantly fewer type 1 "inflammatory" monocytes and the almost complete absence of neutrophils at 12 h and 4 days post-SCI. Together, these results indicate that MyD88/IL-1R1 signals regulate the entry of neutrophils and, to a lesser extent, type I "inflammatory" monocytes at sites of SCI. (C) 2009 Elsevier Inc. All rights reserved.