High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury.
High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury.
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DOI：
10.1016/j.expneurol.2014.01.013
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发表时间：
2014-04
影响因子：
5.3
通讯作者：
Silver, Jerry
中科院分区：
文献类型：
--
作者：
Evans, Teresa A.;Barkauskas, Deborah S.;Myers, Jay T.;Hare, Elisabeth G.;You, Jing Qiang;Ransohoff, Richard M.;Huang, Alex Y.;Silver, Jerry
关键词：
创伤性脊髓损伤后，随着轴突从损伤中心死亡和胶质瘢痕形成，功能缺陷增加。轴突死亡发生在两个阶段：最初的轴突内在阶段发生在最初的几个小时内，第二阶段发生在损伤后的最初几周内。在这里，我们研究了第二期，这是由巨噬细胞浸润的标志。使用强大的时间推移多光子成像，我们捕获的图像之间的相互作用Cx 3cr 1 +/GFP巨噬细胞和小胶质细胞和Thy-1 YFP轴突在小鼠背柱挤压脊髓损伤模型。在损伤后的最初几周内，损伤内的轴突收缩球是静止的，除了当轴突碎片响应于物理接触而通过起泡机制丢失，随后被移动的Cx 3Cr 1 +/GFP细胞吞噬时。利用辐射嵌合体模型来区分骨髓来源的细胞与放射抗性CNS驻留小胶质细胞，我们确定病变中绝大多数累积的细胞来自血液，并且只有这些细胞与轴突损伤相关。有趣的是，CNS驻留Cx 3Cr 1 +/GFP小胶质细胞在这段时间内没有增加积累，也没有参与病变中的神经元破坏。此外，我们发现，血液来源的细胞主要由单标记的Ccr 2 +/RFP巨噬细胞，单标记的Cx 3Cr 1 +/GFP巨噬细胞和少量的双标记细胞组成。由于所有轴突破坏性事件都与Cx 3Cr 1 +/GFP细胞接触，因此我们推断CCR 2单阳性亚群可能不强烈参与轴突枯死。最后，在我们的模型中，删除趋化因子受体CCR 2并没有改变枯死后轴突的位置。了解继发性轴突损伤中涉及的体内细胞相互作用可能导致涉及破坏性浸润血液单核细胞的调制的临床治疗候选者。
After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal die back occurs in two phases: an initial axon intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time lapse multi-photon imaging, we captured images of interactions between Cx3cr1+/GFP macrophages and microglia and Thy-1YFP axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1+/GFP cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1+/GFP microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood-derived cells consisted mainly of singly labeled Ccr2+/RFP macrophages, singly labeled Cx3Cr1+/GFP macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1+/GFP cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes.
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影响因子：
16.2
作者：
Bhaskar, Kiran;Konerth, Megan;Kokiko-Cochran, Olga N.;Cardona, Astrid;Ransohoff, Richard M.;Lamb, Bruce T.
通讯作者：
Lamb, Bruce T.
影响因子：
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作者：
Greer, John E.;Hanell, Anders;Povlishock, John T.
通讯作者：
Povlishock, John T.
影响因子：
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作者：
Jung, S;Aliberti, J;Littman, DR
通讯作者：
Littman, DR
影响因子：
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作者：
Kerschensteiner, M;Schwab, ME;Misgeld, T
通讯作者：
Misgeld, T
影响因子：
25
作者：
Ajami, Bahareh;Bennett, Jami L.;Rossi, Fabio M. V.
通讯作者：
Rossi, Fabio M. V.