Abstract
Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.
Highlights
Ischemia is a broad term to describe a restriction of blood supply to tissues and a key contributing factor to neural damage in the brain and retina, such as that resulted from stroke, diabetes, diabetic retinopathy, glaucoma, etc
To study the chronological changes of retinal immune microenvironment induced by reperfusion injury (RI), we investigated dynamics of immune cell activation and infiltration in the rat retinas
The present study demonstrated in both rat and mouse models that RI induced early microglial activation and macrophage infiltration, and subsequent recruitment of lymphocytes and CD4+ T cells
Summary
Ischemia is a broad term to describe a restriction of blood supply to tissues and a key contributing factor to neural damage in the brain and retina, such as that resulted from stroke, diabetes, diabetic retinopathy, glaucoma, etc. It induces damage to the inner retina and permanent loss of retinal ganglion cells (RGCs) [2, 3]. Microglia are the residential immune competent cells colonized in the central nervous system (CNS) and essential in maintaining the neuro-retinal homeostasis and innate immune defense mechanisms [4, 5]. Under all insults or disease conditions microglia become activated and undergo phenotypic and functional changes, which represents a fundamental innate immune mechanism to protect the retina from infection or injury. Microglial activation is associated with increased production of inflammatory cytokines and oxidative stress, as well as subsequent infiltration of circulating immune cells [10]; they are thought to contribute to the primary early events occurring before neuron death [11, 12]. Given to the importance of microglial activation in ischemia-induced neural pathology, they represent an attractive target for therapeutic interventions
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