Reactive microglia and infiltrating peripheral monocytes have been implicated in many neurodegenerative diseases of the retina and central nervous system (CNS). However, their specific contribution in retinal degeneration remains unclear. We recently showed that peripheral monocytes that infiltrate the retina after ocular injury in mice become permanently engrafted into the tissue, establishing a pro-inflammatory phenotype that promotes neurodegeneration. Here, we show in mice that microglia regulate the process of neuroglia remodeling during ocular injury, and their depletion results in marked upregulation of inflammatory markers, such as Il17f, Tnfsf11, Ccl4, Il1a, Ccr2, Il4, Il5, and Csf2 in the retina, abnormal engraftment of peripheral CCR2 + CX3CR1 + monocytes into the retina and is associated with increased retinal ganglion cell (RGC) loss, retinal nerve fiber layer thinning, and RPE65 + cell migration onto the retinal surface. Furthermore, we show that other types of ocular injuries, such as penetrating corneal trauma and ocular hypertension, also cause similar changes. However, optic nerve crush injury mediated RGC loss evokes neither peripheral monocyte response in the retina, nor RPE65 + cell migration, although peripheral CX3CR1 + and CCR2 + monocytes infiltrate the optic nerve injury site and remain present for months. Our study suggests that microglia are key regulators of peripheral monocyte infiltration and RPE migration and their depletion results in abnormal neuroglia remodeling that exacerbates neuroretinal tissue damage. This mechanism of retinal damage through neuroglia remodeling may be clinically important for the treatment of patients with ocular injuries, including surgical traumas.In this study, we used our CX3CR1 +/EGFP ::CCR2 +/RFP chimera model (28) and CSF1R inhibitor for microglia depletion to investigate the role of peripheral monocytes and microglia in retinal degeneration and inflammatory expression after various types of ocular injuries.
Materials and Methods
Mouse modelsAll animal-based procedures were performed in accordance with the Association For