The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury
The Complement Receptor C5aR Controls Acute Inflammation and Astrogliosis following Spinal Cord Injury
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DOI：
10.1523/jneurosci.5218-14.2015
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发表时间：
2015-04-22
影响因子：
5.3
通讯作者：
Ruitenberg, Marc J.
中科院分区：
文献类型：
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作者：
Brennan, Faith H.;Gordon, Richard;Ruitenberg, Marc J.
本研究探讨了补体激活片段C5a在挫伤脊髓损伤（SCI）后继发病理中的作用。与野生型小鼠相比，缺乏C5a信号受体的C5ar（-/-）小鼠在脊髓损伤第一周表现出运动恢复改善和炎症减少的迹象。有趣的是，C5ar（-/-）小鼠恢复改善的早期迹象从第14天开始恶化，在脊髓损伤第35天，缺乏C5ar最终导致功能结果更差，病变体积更大，髓磷脂含量减少，炎症更广泛。在脊髓损伤后的前7天，用选择性拮抗剂（C5aR- a）对C5aR进行药物阻断，与药物处理的小鼠相比，可以改善恢复，并且这种表型持续到损伤后35天。与C5ar（-/-）小鼠的观察结果一致，如果C5ar - a继续给药到脊髓损伤的更慢性阶段，这些改善就会消失。因此，通过C5a-C5aR轴的信号在急性期似乎是有害的，但在脊髓损伤急性期后起到保护和/或修复作用。在骨髓嵌合小鼠中的进一步实验表明，C5aR在脊髓损伤预后中的双重和相反作用主要与它在中枢驻守细胞上的表达有关，而不是浸润到白细胞上。另外的体内和体外研究提供了直接证据，表明急性期后星形胶质细胞增生、肥大和胶质瘢痕形成需要C5aR信号。总的来说，这些发现强调了脊髓损伤炎症反应的复杂性，并强调了优化治疗干预时机的重要性。
This study investigated the role of the complement activation fragment C5a in secondary pathology following contusive spinal cord injury (SCI). C5ar(-/-) mice, which lack the signaling receptor for C5a, displayed signs of improved locomotor recovery and reduced inflammation during the first week of SCI compared with wild-type mice. Intriguingly, the early signs of improved recovery in C5ar(-/-) mice deteriorated from day 14 onward, with absence of C5aR ultimately leading to poorer functional outcomes, larger lesion volumes, reduced myelin content, and more widespread inflammation at 35 d SCI. Pharmacological blockade of C5aR with a selective antagonist (C5aR-A) during the first 7 d after SCI improved recovery compared with vehicle-treated mice, and this phenotype was sustained up to 35 d after injury. Consistent with observations made in C5ar(-/-) mice, these improvements were, however, lost if C5aR-A administration was continued into the more chronic phase of SCI. Signaling through the C5a-C5aR axis thus appears injurious in the acute period but serves a protective and/or reparative role in the post-acute phase of SCI. Further experiments in bone marrow chimeric mice suggested that the dual and opposing roles of C5aR on SCI outcomes primarily relate to its expression on CNS-resident cells and not infiltrating leukocytes. Additional in vivo and in vitro studies provided direct evidence that C5aR signaling is required during the postacute phase for astrocyte hyperplasia, hypertrophy, and glial scar formation. Collectively, these findings highlight the complexity of the inflammatory response to SCI and emphasize the importance of optimizing the timing of therapeutic interventions.