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

 描述(申请人提供)：沃勒变性(WD)在外周和中枢神经损伤和疾病的模型中得到了广泛的研究。WD是切断或挤压外周神经元轴突，导致远端轴突变性和清除的过程。远端断端的变性是轴突再生过程中必不可少的准备阶段。中枢神经系统的神经再生比周围神经系统慢得多，这是因为它清除阻碍再生的抑制分子的效率很低。在外周，渗透的CCR2+巨噬细胞被认为是损伤后清除神经碎片吞噬必不可少的细胞。因此，当我发现CCR2-/-小鼠缺乏渗透血源性巨噬细胞所需的受体时，我感到惊讶的是，在坐骨神经切断7天后，CCR2-/-小鼠的髓鞘和轴突清除能力与野生型小鼠相当。这些结果的含义是，尽管渗透CCR2+巨噬细胞可能足以清除神经碎片，但它们并不是必需的；也许这些巨噬细胞的缺失可以通过增强“次级”吞噬细胞的吞噬活性来补偿。我提出了几个细胞候选细胞来发挥这种代偿作用：驻留巨噬细胞可以方便地稳定在神经内膜中，占坐骨神经细胞总数的9%，在神经损伤后，据报道它们可以促进细胞的增殖和吞噬。CX3CR1+CCR2-浸润性巨噬细胞虽然在功能上不同于正常情况下的CCR2+巨噬细胞，但可以呈现炎症表型并活跃地吞噬细胞碎片。雪旺细胞与WD和再生有着千丝万缕的联系，参与巨噬细胞的趋化和活化、吞噬、清除、抗原呈递和定向轴突再生。这三个候选细胞拥有在没有CCR2+巨噬细胞渗透的情况下完成有效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检查每个细胞对WD的贡献，以揭示更多关于有机体克服缺陷的非凡能力的信息。目的是为了更好地了解周围神经损伤后的退变和再生过程，以便制定更有效的治疗策略。研究周围神经系统的变性将使我能够将其与中枢神经系统中的细胞相比较，这将为如何促进受损神经的有效退化提供洞察力，以促进更快的神经再生。

 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.