Microglia/Macrophages and CD4+CD25+ T Cells Enhance the Ability of Injury-Activated Lymphocytes to Reduce Traumatic Optic Neuropathy In Vitro.

Yiqun Geng,Nico Van Rooijen,Ye Zhi,Zhihao Lu,Jitian Guan

doi:10.3389/fimmu.2021.687898

Abstract

Inflammation after acute CNS injury plays a dual role. The interplay between immune cells and inflammatory mediators is critical to the outcome of injured neurons. Microglia/macrophages are the first sensors and regulators of the immune response. We previously found that the enhancement of macrophages on neuron survival does not persist in thymectomized rats. How T lymphocytes and macrophages interact and benefit neuron survival is not fully elucidated. To this point, we introduce and characterize a cell-retina co-culture model that mimics the recruitment of peripheral lymphocytes at the injury site. Three-day post-optic nerve transection (ONT) in Fischer 344 rats, transected retinas were co-cultured with either peripheral lymph node-derived lymphocytes (injury-activated) or from intact rats as the control. The injury-activated lymphocytes preserved retinal ganglion cells (RGCs) and caused extensive retina microglial/macrophage infiltration. CD4+CD25+ T cells were upregulated in the injury-activated lymphocytes and increased RGC survival, suggesting that CD4+CD25+ T cells suppressed the cytotoxicity of control lymphocytes. When microglia/macrophages were depleted by clodronate, neuron loss was more extensive, the cytotoxicity of control lymphocytes on RGCs was alleviated, and the neuroprotective effect of injury-activated lymphocytes remain unchanged Cytokine detection showed an increase in IL-6 and TNF-α levels that were reduced with microglia/macrophage depletion. Our results suggest that microglial/macrophage infiltration into axotomized retinas promotes RGC survival by secreting cytokines to induce CD4+CD25+ T cells and suppress T cell-mediated RGC toxicity. These findings reveal a specific role for microglia/macrophage and CD4+CD25+ T cells in inflammation after CNS injury, thereby adding to the mechanistic basis for the development of microglial/macrophage modulation therapy for traumatic CNS injury.

Highlights

IntroductionConcerning injury of the optic nerve, traumatic optic neuropathy or glaucoma results in loss of retinal ganglion cells and loss of vision
Injury to the mature central nervous system (CNS) eventually leads to neuron loss
Results presented here indicate that both proinflammatory microglia/macrophage and peripheral T lymphocytes are activated and are beneficial for the restoration of injured neurons at the subacute stage of optic nerve injury

Summary

Introduction

Concerning injury of the optic nerve, traumatic optic neuropathy or glaucoma results in loss of retinal ganglion cells and loss of vision. We previously reported that zymosan-induced microglia/macrophage activation improves axotomized retinal ganglion cell (RGC) survival in vivo in both F344 rats and experimental autoimmune encephalomyelitissusceptible Lewis rats, but not in thymectomized rats [6]. This indicates that microglia/macrophages participate in crosstalk with T cells to affect the survival of neurons [7], but the process has yet to be elucidated. We use an axotomized retina and lymph node-derived lymphocyte co-culture model to mimic the peripheral immune cell infiltration, and the consequent interaction with resident microglia/macrophages, to understand how the outcome of axotomized RGCs is affected

Methods

Results

Conclusion