W. M. Keck Center for Collaborative Neuroscience, Department of Cell Biology and Neuroscience, Rutgers, The State University of New Jersey, Piscataway, New Jersey, United States of America.
PLoS One. 2010 Feb 23;5(2):e9380. doi: 10.1371/journal.pone.0009380.
Inflammatory response following central nervous system (CNS) injury contributes to progressive neuropathology and reduction in functional recovery. Axons are sensitive to mechanical injury and toxic inflammatory mediators, which may lead to demyelination. Although it is well documented that degenerated myelin triggers undesirable inflammatory responses in autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), there has been very little study of the direct inflammatory consequences of damaged myelin in spinal cord injury (SCI), i.e., there is no direct evidence to show that myelin debris from injured spinal cord can trigger undesirable inflammation in vitro and in vivo. Our data showed that myelin can initiate inflammatory responses in vivo, which is complement receptor 3 (CR3)-dependent via stimulating macrophages to express pro-inflammatory molecules and down-regulates expression of anti-inflammatory cytokines. Mechanism study revealed that myelin-increased cytokine expression is through activation of FAK/PI3K/Akt/NF-kappaB signaling pathways and CR3 contributes to myelin-induced PI3K/Akt/NF-kappaB activation and cytokine production. The myelin induced inflammatory response is myelin specific as sphingomyelin (the major lipid of myelin) and myelin basic protein (MBP, one of the major proteins of myelin) are not able to activate NF-kappaB signaling pathway. In conclusion, our results demonstrate a crucial role of myelin as an endogenous inflammatory stimulus that induces pro-inflammatory responses and suggest that blocking myelin-CR3 interaction and enhancing myelin debris clearance may be effective interventions for treating SCI.
中枢神经系统（CNS）损伤后的炎症反应导致进行性神经病理学和功能恢复减少。轴突对机械损伤和毒性炎症介质敏感，这可能导致脱髓鞘。尽管已经有充分的文献证明，在多发性硬化症（MS）及其动物模型实验性自身免疫性脑脊髓炎（EAE）等自身免疫性疾病中，退化的髓磷脂会引发不良的炎症反应，但对于脊髓损伤（SCI）中受损髓磷脂的直接炎症后果，即没有直接证据表明来自损伤脊髓的髓磷脂碎片可以在体外和体内引发不良炎症，研究甚少。我们的数据表明，髓磷脂可以在体内引发炎症反应，这是通过刺激巨噬细胞表达促炎分子并下调抗炎细胞因子的表达来依赖补体受体 3（CR3）的。机制研究表明，髓磷脂增加细胞因子表达是通过激活 FAK/PI3K/Akt/NF-κB 信号通路，而 CR3 有助于髓磷脂诱导的 PI3K/Akt/NF-κB 激活和细胞因子产生。髓磷脂诱导的炎症反应是髓磷脂特异性的，因为鞘磷脂（髓磷脂的主要脂质）和髓鞘碱性蛋白（MBP，髓磷脂的主要蛋白质之一）不能激活 NF-κB 信号通路。总之，我们的结果表明，髓磷脂作为一种内源性炎症刺激物，可诱导促炎反应，并表明阻断髓磷脂-CR3 相互作用和增强髓磷脂碎片清除可能是治疗 SCI 的有效干预措施。
