Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β mediates microglial phagocytosis of degenerating axons.
Toll/interleukin-1 receptor domain-containing adapter inducing interferon-β mediates microglial phagocytosis of degenerating axons.
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DOI：
10.1523/jneurosci.0203-12.2012
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发表时间：
2012-05-30
期刊：
影响因子：
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通讯作者：
Venkatesan A
中科院分区：
文献类型：
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作者：
Hosmane S;Tegenge MA;Rajbhandari L;Uapinyoying P;Ganesh Kumar N;Thakor N;Venkatesan A
在中枢神经系统（CNS）损伤后，受损内源性组织的小胶质细胞吞噬被认为在恢复和再生中起重要作用。以前的工作主要集中在描述神经元和髓磷脂清除的机制。然而，对轴突碎片吞噬作用的机制知之甚少。我们开发了一种新的微流控平台，可以使小胶质细胞与中枢神经系统轴突束共培养，以研究小胶质细胞吞噬轴突的机制。利用这个平台，我们发现轴突变性导致小胶质细胞内1型干扰素基因的诱导。TRIF（一种toll样受体衔接蛋白）的药理学和遗传破坏可阻断干扰素反应的诱导并抑制轴突碎片的小胶质吞噬。在体内，TRIF基因缺失的小鼠，背根轴突切开术后轴突的小胶质细胞吞噬功能受损。此外，我们发现p38mito原活化蛋白激酶（MAPK）级联是轴突退化后TRIF下游的信号通路，并发现SB203580抑制p38MAPK也阻断了轴突碎片的清除。最后，我们发现trf依赖的小胶质细胞清除无髓鞘轴突碎片有助于轴突的生长。总之，我们提供的证据表明，trif介导的信号在小胶质细胞清除轴突碎片中发挥了意想不到的作用，从而促进了轴突生长更宽松的环境。我们的研究对于以中枢神经系统轴突变性为特征的许多创伤性、神经炎症和神经退行性疾病的新型再生和恢复策略的发展具有重要意义。
Following central nervous system (CNS) injury, microglial phagocytosis of damaged endogenous tissue is thought to play an important role in recovery and regeneration. Previous work has focused on delineating mechanisms of clearance of neurons and myelin. Little, however, is known of the mechanisms underlying phagocytosis of axon debris. We have developed a novel microfluidic platform that enables co-culture of microglia with bundles of CNS axons in order to investigate mechanisms of microglial phagocytosis of axons. Utilizing this platform, we find that axon degeneration results in the induction of type-1 interferon genes within microglia. Pharmacologic and genetic disruption of TRIF, a toll-like receptor adaptor protein, blocks induction of the interferon response and inhibits microglial phagocytosis of axon debris in vitro. In vivo, microglial phagocytosis of axons following dorsal root axotomy is impaired in mice in which TRIF has been genetically deleted. Furthermore, we identify the p38mitogen-activated protein kinase (MAPK) cascade as a signaling pathway downstream of TRIF following axon degeneration and find that inhibition of p38MAPK by SB203580 also blocked clearance of axon debris. Finally, we find that TRIF-dependent microglial clearance of unmyelinated axon debris facilitates axon outgrowth. Overall, we provide evidence that TRIF-mediated signaling plays an unexpected role in axonal debris clearance by microglia, thereby facilitating a more permissive environment for axonal outgrowth. Our study has significant implications for the development of novel regenerative and restorative strategies for the many traumatic, neuroinflammatory, and neurodegenerative conditions characterized by CNS axon degeneration.