Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease
Microglia and macrophage activation and the regulation of complement-receptor-3 (CR3/MAC-1)-mediated myelin phagocytosis in injury and disease
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DOI：
10.1385/jmn:21:1:65
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发表时间：
2003-01-01
影响因子：
3.1
通讯作者：
Rotshenker, S
中科院分区：
文献类型：
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作者：
Rotshenker, S
小胶质细胞和巨噬细胞在中枢和周围神经系统（分别为 CNS 和 PNS）对损伤和疾病的反应中发挥着关键作用，其中之一是通过吞噬作用去除退化的髓磷脂。髓磷脂去除在华勒变性（PNS 轴突损伤后发生）和 CNS 自身免疫性脱髓鞘疾病（例如多发性硬化症）中是有效的，但在 CNS 轴突损伤后效率低下。我们认为，髓鞘质去除效率低下是由于小胶质细胞活化不足所致，反映为未能上调 Galectin-3/MAC-2 表达，这标志着与有效髓鞘质吞噬作用相关的活化状态。令人惊讶的是，无论是否执行髓磷脂吞噬作用，中枢神经系统小胶质细胞都表达α（M）/β（2）整合素补体受体-3（CR3/MAC-1），其具有介导有效髓磷脂吞噬作用的潜力。我们假设 CR3/MAC-1 可能以不同的非活性和活性状态存在，分别决定 CR3/MAC-1 介导的髓磷脂吞噬作用的有效和低效。我们提供的证据表明 CR3/MAC-1 介导的髓磷脂吞噬作用在小胶质细胞和巨噬细胞中受到调节。首先，CR3/MAC-1介导的髓磷脂吞噬作用具有补体依赖性和非补体依赖性成分。其次，活跃的补体系统增强 CR3/MAC-1 介导的髓磷脂吞噬作用。第三，在存在和不存在活性补体系统的情况下，抗α(M)单克隆抗体(MAb)抑制CR3/MAC-1介导的髓磷脂吞噬作用，抗β(2)单克隆抗体增强CR3/MAC-1介导的髓磷脂吞噬作用。第四，活性补体系统调节 MAb 诱导的 CR3/MAC-1 介导的髓磷脂吞噬作用。总体而言，MAb 诱导的吞噬作用调节范围可能从低效到高效三到七倍。我们认为 MAb 诱导的吞噬作用调节的机制之一是诱导/稳定非活性和活性构象变化。单克隆抗体诱导的吞噬作用调节必须揭示天然细胞外分子结合并调节小胶质细胞和巨噬细胞中 CR3/MAC-1 介导的髓鞘质吞噬作用的机制。
Microglia and macrophages play critical roles in the response of the central and peripheral nervous systems (CNS and PNS, respectively) to injury and disease, one of which is the removal of degenerated myelin by phagocytosis. Myelin removal is efficient during Wallerian degeneration, which follows injury to PNS axons, and in CNS autoimmune demyelinating diseases (e.g., multiple sclerosis) but is inefficient after injury to CNS axons. We suggest that inefficient myelin removal results from deficient microglia activation, reflected by the failure to up-regulate Galectin-3/MAC-2 expression, which marks a state of activation correlated with efficient myelin phagocytosis. Surprisingly, whether or not executing myelin phagocytosis, CNS microglia express the alpha(M)/beta(2) integrin complement receptor-3 (CR3/MAC-1), which has the potential of mediating efficient myelin phagocytosis. We hypothesize that CR3/MAC-1 might be present in distinct inactive and active states that determine, respectively, efficient and inefficient CR3/MAC-1-mediated myelin phagocytosis. We present evidence that CR3/MAC-1-mediated myelin phagocytosis is regulated in microglia and macrophages. First, CR3/MAC-1-mediated myelin phagocytosis has complement-dependent and -independent components. Second, an active complement system augments CR3/MAC-1-mediated myelin phagocytosis. Third, anti-alpha(M) monoclonal antibodies (MAbs) inhibit and anti-beta(2) MAbs augment CR3/MAC-1-mediated myelin phagocytosis in the presence and absence of an active complement system. Fourth, an active complement system modulates MAb-induced regulation of CR3/MAC-1-mediated myelin phagocytosis. Overall, MAb-induced phagocytosis regulation might range three- to sevenfold from inefficient to efficient. We suggest that one of the mechanisms underlying MAb-induced phagocytosis regulation is the induction/stabilization of inactive and active conformational changes. Monoclonal antibody-induced phagocytosis regulation must reveal a mechanism by which native extracellular molecules bind to and regulate CR3/MAC-1-mediated myelin phagocytosis in microglia and macrophages.