Brennan Faith H, Gordon Richard, Lao Hong W, Biggins Patrick J, Taylor Stephen M, Franklin Robin J M, Woodruff Trent M, Ruitenberg Marc J
School of Biomedical Sciences, University of Queensland, Brisbane, 4072, Australia.
Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute & Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0AH, United Kingdom.
J Neurosci. 2015 Apr 22;35(16):6517-31. doi: 10.1523/JNEUROSCI.5218-14.2015.
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.
本研究调查了补体激活片段C5a在脊髓挫伤性损伤（SCI）后继发性病理过程中的作用。缺乏C5a信号受体的C5ar(-/-)小鼠与野生型小鼠相比，在SCI后的第一周表现出运动恢复改善和炎症减轻的迹象。有趣的是，C5ar(-/-)小鼠恢复改善的早期迹象从第14天开始恶化，最终缺乏C5aR导致35天时功能结局更差、损伤体积更大、髓磷脂含量减少以及炎症更广泛。与给予赋形剂处理的小鼠相比，在SCI后前7天用选择性拮抗剂（C5aR-A）对C5aR进行药理学阻断可改善恢复情况，且这种表型在损伤后35天仍持续存在。然而，与在C5ar(-/-)小鼠中观察到的情况一致，如果在SCI的更慢性期继续给予C5aR-A，这些改善就会消失。因此，通过C5a-C5aR轴的信号传导在急性期似乎具有损害作用，但在SCI的急性后期发挥保护和/或修复作用。对骨髓嵌合小鼠进行的进一步实验表明，C5aR对SCI结局的双重且相反的作用主要与其在中枢神经系统驻留细胞上的表达有关，而非浸润的白细胞。额外的体内和体外研究提供了直接证据，表明在急性后期星形胶质细胞增生、肥大和胶质瘢痕形成需要C5aR信号传导。总的来说，这些发现突出了对SCI炎症反应的复杂性，并强调了优化治疗干预时机的重要性。
