A Critical Role for Macrophages Near Axotomized Neuronal Cell Bodies in Stimulating Nerve Regeneration

Abstract

Macrophages have been implicated in peripheral nerve regeneration for some time, supposedly through their involvement in Wallerian degeneration, the process by which the distal nerve degenerates after axotomy and is cleared by phagocytosis. Thus, in several studies in which macrophage accumulation in the distal nerve was reduced and Wallerian degeneration inhibited, regeneration was delayed. However, this interpretation ignores the more recent findings that macrophages also accumulate around axotomized cell bodies. The function of macrophage action at this second site has not been clear. In two mutant strains of mice, the slow Wallerian degeneration (Wld s ) mouse and the chemokine receptor CCR2 knock-out mouse, we report that macrophage accumulation after axotomy was abolished in both the dorsal root ganglion (DRG) and the distal sciatic nerve. To measure neurite outgrowth, DRG neurons were given a conditioning lesion, and outgrowth was measured in vitro 7 d later in the absence of the distal nerve segment. The increased growth normally seen after a conditioning lesion did not occur or was reduced in Wld s or CCR2 Ϫ/Ϫ mice. In the superior cervical ganglion (SCG), particularly in Wld s mice, macrophage accumulation was reduced but not abolished after axotomy. In SCG neurons from Wld s mice, the conditioning lesion response was unchanged; however, in CCR2 Ϫ/Ϫ mice in which the effect on macrophage accumulation was greater, SCG neurite outgrowth was significantly reduced. These results indicate that macrophages affect neurite outgrowth by acting at the level of peripheral ganglia in addition to any effects they might produce by facilitation of Wallerian degeneration.

AlphaB-crystallin regulates remyelination after peripheral nerve injury

“…This inadequate axon regrowth led to the suggestion that, although regeneration would eventually proceed, albeit slowly, a rapid course of Wallerian degeneration is necessary if axons are to regenerate at optimal rates and maximum extent (41). More recently, Niemi et al (42) found that, in addition to delayed Wallerian degeneration, reduced PNS regeneration in injured Ola animals seems to be related to defects at the level of the neuronal cell body, because neurite outgrowth is impaired if macrophages and their products are reduced or absent. This idea of early PNS injury events impacting later processes extends to other functions, such as Schwann cell redifferentiation and remyelination.…”

CCR2 Deficiency Impairs Macrophage Infiltration and Improves Cognitive Function after Traumatic Brain Injury

“…In contrast to our findings, others have shown a beneficial role for CCR2 in a model where CCR2-dependent macrophages were critical for nerve regeneration following axotomy. 60 It is possible that CCR2 plays different roles depending on the site and mechanism of injury. A greater understanding of the mechanisms, cellular subsets, timing, and environmental cues should clarify our understanding of this molecule and of the cells on which it is expressed.…”

Sensing nerve injury at the axonal ER: Activated Luman/CREB3 serves as a novel axonally synthesized retrograde regeneration signal

“…dorsal root ganglion | transcription factor | axotomy | sensory neuron A complex series of cellular and molecular events participates in reprogramming sensory neurons as they transition to a regenerating state following peripheral nerve injury (1)(2)(3)(4)(5)(6)(7). Injury discharge and rapid ion fluxes initiate this transition, followed by the loss of target-derived signals and receipt of retrograde signals from the site of injury (8)(9)(10).…”