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

Case Western Reserve University, Cleveland OH

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Abstract

? 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.