How is Wallerian degeneration accomplished in the absence of CCR2+ infiltrating macrophages?

 描述（由申请人提供）：沃勒变性（WD）已在外周和中枢神经损伤和疾病模型中进行了广泛研究。WD是外周神经元轴突的横断或压碎导致远端轴突节段变性和清除的过程。切断的远端片段的变性是轴突再生过程的重要准备阶段。由于中枢神经系统清除阻碍再生的抑制性分子的效率低，因此中枢神经系统的神经再生比外周神经系统慢得多。 在外周，浸润的CCR 2+巨噬细胞被认为是损伤后神经碎片吞噬清除所不可或缺的。因此，当我发现缺乏造血巨噬细胞浸润所必需的受体的CCR 2-/-小鼠在坐骨神经横断后7天显示出与野生型小鼠相当的髓鞘和轴突清除率时，我感到惊讶。 这些结果的含义是，虽然浸润的CCR 2+巨噬细胞可能足以清除神经碎片，但它们不是必需的;并且这些巨噬细胞的缺失可能通过“次级”吞噬细胞的吞噬活性增加来补偿。 我提出了几个细胞候选人的这种补偿作用：居民巨噬细胞是方便地在神经内膜和代表高达9%的坐骨神经的细胞群体，神经损伤后，他们已被报道增加增殖和吞噬作用。CX 3CR 1 + CCR 2-浸润巨噬细胞，尽管在正常条件下与CCR 2+巨噬细胞功能不同，但可以呈现炎性表型并积极吞噬碎片。雪旺细胞与WD和再生有着千丝万缕的联系，并参与巨噬细胞的趋化性和活化、吞噬作用、清除、抗原呈递和定向轴突再生。 这三种候选细胞具有在不存在浸润的CCR 2+巨噬细胞的情况下实现有效WD的分子机制，但它们的行为从根本上取决于独特的组织环境。因此，我将使用体外和体内方法研究每个细胞对WD的贡献，以揭示更多关于生物体克服缺陷的非凡能力的信息。 我的目标是更好地了解周围神经损伤后的退行性和再生过程，以制定更有效的治疗策略。研究周围神经系统中的变性将使我能够与中枢神经系统中的细胞对应物进行比较，这将为如何促进受损神经的有效变性以促进更快的神经再生提供见解。

 DESCRIPTION (provided by applicant): Wallerian degeneration (WD) has been extensively studied in models of peripheral and central nerve injuries and diseases. WD is the process by which transection or crushing of the axons of peripheral neurons leads to degeneration and clearance of the distal axonal segment. Degeneration of the severed distal fragment is an essential preparatory stage for the process of axonal regeneration. Nerve regeneration occurs much more slowly in the central nervous system than in the peripheral nervous system due to its low efficiency of clearance of inhibitory molecules that obstruct regrowth. In the periphery, infiltrating CCR2+ macrophages are thought to be indispensible for nerve debris phagocytosis clearance after injury. It was therefore surprising when I discovered that the CCR2-/- mouse, which lacks the necessary receptor for infiltration of hematogenous macrophages, displayed comparable myelin and axonal clearance to wild type mice 7 days after sciatic nerve transection. The implication of these results is that though infiltrating CCR2+ macrophages may be sufficient for nerve debris clearance, they are not necessary; and perhaps the absence of these macrophages is compensated with increased phagocytic activity of a "secondary" phagocyte. I propose several cell candidates for this compensatory role: resident macrophages are conveniently poised in the endoneurium and represent up to 9% of the cellular population in the sciatic nerve where, after nerve injury, they have been reported to increase proliferation and phagocytosis. CX3CR1+CCR2- infiltrating macrophages, though functionally different than CCR2+ macrophages under normal conditions, can assume an inflammatory phenotype and actively phagocytose debris. Schwann cells are inextricably linked to WD and regeneration and have a hand in macrophage chemotaxis and activation, phagocytosis, clearance, antigen presentation, and directed axon regrowth. These three cell candidates possess the molecular machinery to accomplish efficient WD in the absence of infiltrating CCR2+ macrophages, but their behavior is fundamentally dependent upon the unique tissue environment. I will therefore examine each cell's contribution to WD using in vitro and in vivo approaches to uncover more information regarding an organism's remarkable ability to overcome deficit. I aim to better understand the degenerative and regenerative processes after peripheral nerve injury in order to develop more effective treatment strategies. Studying degeneration in the peripheral nervous system will allow me to draw parallels to the cellular counterparts in the central nervous system that will provide insight into how to facilitate effective degeneration of damaged nerves to promote faster nerve regeneration.