Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury.
Perturbing chondroitin sulfate proteoglycan signaling through LAR and PTPσ receptors promotes a beneficial inflammatory response following spinal cord injury.
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DOI：
10.1186/s12974-018-1128-2
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发表时间：
2018-03-20
影响因子：
9.3
通讯作者：
Karimi-Abdolrezaee S
中科院分区：
文献类型：
--
作者：
Dyck S;Kataria H;Alizadeh A;Santhosh KT;Lang B;Silver J;Karimi-Abdolrezaee S
创伤性脊髓损伤（SCI）导致硫酸软骨素蛋白聚糖（CSPG）通过反应性胶质细胞上调，从而阻碍脊髓的修复和再生。已知CSPG的降解有利于促进内源性修复机制，包括轴突发芽/再生、少突胶质细胞替代和髓鞘再生，并且与SCI后功能结果的改善相关。最近的证据表明，CSPGs可能通过调节SCI后的神经炎症来调节继发性损伤机制。到目前为止，CSPG在SCI神经炎症中的作用在很大程度上仍未被探索。CSPG特异性受体、白细胞共同抗原相关受体（LAR）和蛋白酪氨酸磷酸酶-σ受体（PTPσ）的发现，有助于阐明CSPG在SCI中的细胞和分子机制。在本研究中，我们采用了体内和体外平行的方法来剖析CSPGs及其受体LAR和PTPσ在SCI急性和亚急性期炎症过程中的调节作用。在雌性Sprague道利大鼠的临床相关的压迫性SCI模型中，我们分别通过两种细胞内功能阻断肽（称为ILP和ISP）靶向LAR和PTPσ。我们在SCI后的不同时间点通过渗透性微型泵以可持续的方式向受损脊髓鞘内注射ILP和ISP治疗。我们采用流式细胞术，蛋白质印迹，免疫组织化学在大鼠脊髓损伤，以及补充在原代小胶质细胞培养的体外研究，以解决我们的问题。我们提供了新的证据表明LAR和PTPσ受体在SCI中具有关键的免疫调节作用。我们发现，阻断LAR和PTPσ减少了经典活化的M1小胶质细胞/巨噬细胞的数量，同时促进了交替活化的M2小胶质细胞/巨噬细胞和T调节细胞。这种转变与促再生免疫介质白细胞介素-10（IL-10）和精氨酸酶-1显著升高相关。我们在小胶质细胞中的平行体外研究发现，虽然CSPG本身不诱导M1表型，但它们促进促炎表型。有趣的是，抑制M1和M2小胶质细胞中的LAR和PTPσ在CSPG存在下积极调节它们的炎症反应，并利用它们的吞噬和动员能力。有趣的是，我们的研究结果表明，CSPG调节小胶质细胞，至少部分地，通过激活LAR和PTPσ下游的Rho/ROCK通路。我们揭示了LAR和PTPσ在创伤性SCI中调节神经炎症的新作用。我们的研究结果提供了新的见解CSPG信号的操纵机制，可以促进SCI的恢复。更重要的是，这项工作介绍了ILP/ISP作为一种可行的策略，用于调节SCI和其他中枢神经系统神经炎症条件下的免疫反应的潜力。本文的在线版本（10.1186/s12974-018-1128-2）包含补充材料，可供授权用户使用。
Traumatic spinal cord injury (SCI) results in upregulation of chondroitin sulfate proteoglycans (CSPGs) by reactive glia that impedes repair and regeneration in the spinal cord. Degradation of CSPGs is known to be beneficial in promoting endogenous repair mechanisms including axonal sprouting/regeneration, oligodendrocyte replacement, and remyelination, and is associated with improvements in functional outcomes after SCI. Recent evidence suggests that CSPGs may regulate secondary injury mechanisms by modulating neuroinflammation after SCI. To date, the role of CSPGs in SCI neuroinflammation remains largely unexplored. The recent discovery of CSPG-specific receptors, leukocyte common antigen-related (LAR) and protein tyrosine phosphatase-sigma (PTPσ), allows unraveling the cellular and molecular mechanisms of CSPGs in SCI. In the present study, we have employed parallel in vivo and in vitro approaches to dissect the role of CSPGs and their receptors LAR and PTPσ in modulating the inflammatory processes in the acute and subacute phases of SCI. In a clinically relevant model of compressive SCI in female Sprague Dawley rats, we targeted LAR and PTPσ by two intracellular functionally blocking peptides, termed ILP and ISP, respectively. We delivered ILP and ISP treatment intrathecally to the injured spinal cord in a sustainable manner by osmotic mini-pumps for various time-points post-SCI. We employed flow cytometry, Western blotting, and immunohistochemistry in rat SCI, as well as complementary in vitro studies in primary microglia cultures to address our questions. We provide novel evidence that signifies a key immunomodulatory role for LAR and PTPσ receptors in SCI. We show that blocking LAR and PTPσ reduces the population of classically activated M1 microglia/macrophages, while promoting alternatively activated M2 microglia/macrophages and T regulatory cells. This shift was associated with a remarkable elevation in pro-regenerative immune mediators, interleukin-10 (IL-10), and Arginase-1. Our parallel in vitro studies in microglia identified that while CSPGs do not induce an M1 phenotype per se, they promote a pro-inflammatory phenotype. Interestingly, inhibiting LAR and PTPσ in M1 and M2 microglia positively modulates their inflammatory response in the presence of CSPGs, and harnesses their ability for phagocytosis and mobilization. Interestingly, our findings indicate that CSPGs regulate microglia, at least in part, through the activation of the Rho/ROCK pathway downstream of LAR and PTPσ. We have unveiled a novel role for LAR and PTPσ in regulating neuroinflammation in traumatic SCI. Our findings provide new insights into the mechanisms by which manipulation of CSPG signaling can promote recovery from SCI. More importantly, this work introduces the potential of ILP/ISP as a viable strategy for modulating the immune response following SCI and other neuroinflammatory conditions of the central nervous system. The online version of this article (10.1186/s12974-018-1128-2) contains supplementary material, which is available to authorized users.
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影响因子：
4.6
作者：
Bollaerts I;Van Houcke J;Andries L;De Groef L;Moons L
通讯作者：
Moons L
影响因子：
2.9
作者：
GREEN, LC;WAGNER, DA;TANNENBAUM, SR
通讯作者：
TANNENBAUM, SR
软骨素酶ABC促进脊髓损伤后完整和受伤的脊柱系统的发芽。
DOI：
10.1523/jneurosci.2980-06.2006
发表时间：
2006-10-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Barritt AW;Davies M;Marchand F;Hartley R;Grist J;Yip P;McMahon SB;Bradbury EJ
通讯作者：
Bradbury EJ
影响因子：
4.2
作者：
Fehlings, Michael G.;Theodore, Nicholas;McKerracher, Lisa
通讯作者：
McKerracher, Lisa
影响因子：
5.3
作者：
Bartus, Katalin;James, Nicholas D.;Bradbury, Elizabeth J.
通讯作者：
Bradbury, Elizabeth J.