Treatment of the adult retina with microglia-suppressing factors retards axotomy-induced neuronal degradation and enhances axonal regeneration in vivo and in vitro

Abstract

To monitor the cascade of events initiated by injury of adult neurons, and to explore whether and how neighboring microglial cells contribute to the degradation of lesioned neurons, axotomy-induced ganglion cell degeneration was investigated in adult rats. Suppression of macrophage and microglia activity during the weeks following transection of the optic nerve was performed with the immunoglobulin-derived tripeptide Thr-Lys-Pro, which is a macrophage inhibitory factor (MIF) and retards the activity of cells of monocytic origin. Single or repeated injection of MIF into the vitreous body during and after transection of the optic nerve resulted in significant retardation of axotomy-induced ganglion cell degradation in the retina as detected by specific labeling with the retrogradely transported fluorescent dye 4Di-10ASP. MIF specifically altered the morphology of labeled microglial cells from a ramified to an oval, less ramified shape, indicating that these cells were targets of its activity. Injection of the tetrapeptide macrophage stimulating factor, also known as tuftsin (Thr-Lys-Pro-Arg), revealed effects opposite to those described for the MIF: it increased the number of labeled microglial cells and enhanced the devastating effects of axotomy on ganglion cells. The viability of rescued ganglion cells in retinas treated with the various drugs was assessed both in vivo and in vitro. (1) Intravitreal injection of MIF to prevent degradation of neurons combined with transplantation of autologous peripheral nerve grafts, which facilitate regrowth of the transected neurites, revealed that significantly more ganglion cells contributed to axonal regeneration (17.1%) than in untreated controls (9.5%). (2) Explantation of retinas that were pretreated with MIF in situ revealed higher incidence of axonal outgrowth in organ cultures than untreated control explants or retinas treated with either the basic fibroblast growth factor or brain-derived neurotrophic factor. The present results demonstrate that axotomy initializes a cascade of microglia-mediated autodestructive retinal responses, which culminate in degradation of "sick," but obviously viable neurons. We postulate that the retinal microglial system has a key role in recognizing and eliminating severed neurons.

Plasminogen activators promote excitotoxicity‐induced retinal damage

“…The results presented above, however, indicate that two different cell types, ganglion cells and microglial cells (73), contribute to the origin of tPA in the retina. Although the exact reason why microglial cells synthesize tPA after KA injection is not clear, they might synthesize tPA and use it to migrate into the inner retina to remove the debris from dying cells (74)(75)(76) but they can contribute also to secondary retinal damage. It is also possible that microglial cells can be migrated into the inner retina independent of tPA up-regulation (32,73,77).…”

A Novel Role for Sema3A in Neuroprotection from Injury Mediated by Activated Microglia

“…Activated microglia have been implicated in demyelinating and neurodegenerative diseases (Itagaki et al, 1989;Lucchinetti et al, 2000;McGeer and McGeer, 2003). There is some experimental support for the proposal that blocking microglia activation may be neuroprotective, for example through the production of trophic factors including NGF and NT3 (Mallat et al, 1989;Thanos et al, 1993;Elkabes et al, 1996;Rabchevsky and Streit, 1997;Lim et al, 2000;Wu et al, 2002;Zhang et al, 2003). Furthermore, the observation that TNF-␣ null mice show increased neuronal death after ischemia in association with reduced microglia recruitment is consistent with microglia-mediated neuroprotection detectedonmicrogliainthecontrollesion(F,H).AfterLPSinjection,Npn-1-andPlexin-1-positivestainingispresentinactivatedmicroglia(G,I).…”

ATP-Induced Non-Neuronal Cell Permeabilization in the Rat Inner Retina

“…Their role is not restricted to a mere removal of damaged and dying neurons. Microglia contribute actively to the degradation of neurons, because it has been shown that suppression of microglial activity results in a retardation of tissue cell death (Thanos et al, 1993;Frade and Barde, 1998).…”