Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury.
Peripherally derived macrophages modulate microglial function to reduce inflammation after CNS injury.
复制标题
DOI：
10.1371/journal.pbio.2005264
复制
发表时间：
2018-10
期刊：
影响因子：
9.8
通讯作者：
David S
中科院分区：
文献类型：
--
作者：
Greenhalgh AD;Zarruk JG;Healy LM;Baskar Jesudasan SJ;Jhelum P;Salmon CK;Formanek A;Russo MV;Antel JP;McGavern DB;McColl BW;David S
浸润性单核细胞衍生的巨噬细胞（MDM）和常驻小胶质细胞占主导地位的中枢神经系统（CNS）损伤部位。这些细胞群在损伤后的不同作用开始被发现。在这里，我们显示的证据表明，MDM和小胶质细胞直接相互沟通和差异调节对方的功能。重要的是，小胶质细胞介导的吞噬作用和炎症被浸润的巨噬细胞抑制。在脊髓损伤（SCI）的情况下，防止这种通信增加小胶质细胞激活和脊髓功能恢复。我们认为，巨噬细胞进入中枢神经系统提供了一种调节机制，控制急性和长期的小胶质细胞介导的炎症，这可能会驱动各种中枢神经系统疾病的损害。免疫系统和中枢神经系统现在被认为是密不可分的。在对损伤的反应中，免疫系统通过分子和细胞介质的复合物来塑造CNS恢复。然而，目前尚不清楚如何利用这种反应的动力学，幅度和组分来改善CNS恢复。支配中枢神经系统病变的两种免疫细胞是常驻的小胶质细胞（在损伤前就已经存在）和浸润的巨噬细胞（在损伤后从血液中进入）。这两种细胞被认为对结果至关重要，但尚不清楚它们是否或如何相互作用。为了研究这一点，我们在小胶质细胞-巨噬细胞共培养系统和创伤性脊髓损伤的体内模型中使用了小鼠和人类细胞。我们发现浸润性巨噬细胞抑制小胶质细胞的关键功能，如清除组织碎片和炎症传播。阻止巨噬细胞-小胶质细胞通讯会增加小胶质细胞的激活并使恢复恶化。我们认为，从血液中浸润的巨噬细胞提供了一种天然的控制机制，对有害的急性和长期的小胶质细胞介导的炎症。外周巨噬细胞的操作可以提供靶向小胶质细胞介导的引起或加重CNS损伤和疾病的机制的治疗性治疗选择。
Infiltrating monocyte-derived macrophages (MDMs) and resident microglia dominate central nervous system (CNS) injury sites. Differential roles for these cell populations after injury are beginning to be uncovered. Here, we show evidence that MDMs and microglia directly communicate with one another and differentially modulate each other’s functions. Importantly, microglia-mediated phagocytosis and inflammation are suppressed by infiltrating macrophages. In the context of spinal cord injury (SCI), preventing such communication increases microglial activation and worsens functional recovery. We suggest that macrophages entering the CNS provide a regulatory mechanism that controls acute and long-term microglia-mediated inflammation, which may drive damage in a variety of CNS conditions. The immune and the central nervous systems are now thought to be inextricably linked. In response to injury, the immune system shapes CNS recovery through a complex of molecular and cellular mediators. However, it is unclear how the kinetics, magnitude, and components of this response can be harnessed to improve CNS restoration. The two immune cells that dominate CNS lesions are resident microglia—already present before the injury—and infiltrating macrophages, which enter from the blood after injury. Both cells are thought to be critical to the outcome, yet it is unknown if, or how, they interact. To investigate this, we used mouse and human cells in microglia–macrophage coculture systems and an in vivo model of traumatic spinal cord injury. We show that infiltrating macrophages suppress key functions of microglia, such as removal of tissue debris and propagation of inflammation. Preventing macrophage–microglia communication increases microglial activation and worsens recovery. We suggest that infiltrating macrophages from the blood provide a natural control mechanism against detrimental acute and long-term microglial-mediated inflammation. Manipulation of the peripheral macrophages may provide a therapeutic treatment option to target microglial-mediated mechanisms that cause or exacerbate CNS injury and disease.
登录
查看更多内容
影响因子：
16.2
作者：
Gadani SP;Walsh JT;Lukens JR;Kipnis J
通讯作者：
Kipnis J
影响因子：
82.9
作者：
Baruch, Kuti;Deczkowska, Aleksandra;Schwartz, Michal
通讯作者：
Schwartz, Michal
影响因子：
6.3
作者：
Denes, Adam;Vidyasagar, Rishma;Allan, Stuart M.
通讯作者：
Allan, Stuart M.
影响因子：
5.3
作者：
Greenhalgh, Andrew D.;David, Samuel
通讯作者：
David, Samuel
影响因子：
25
作者：
Davalos, D;Grutzendler, J;Gan, WB
通讯作者：
Gan, WB