The role and origin of microglia in retinal neurodegenerative disorders

Abstract

Microglia are the mononuclear phagocytes in the central nervous system (CNS), which constitute the first defense line of the innate immune system. In neurodegenerative disorders, microglia react rapidly and exert protective roles by scavenging pathogens and cell debris. However, the over-activated microglia in chronic neurodegenerative disorders produce pro-inflammatory cytokines and exacerbate neuronal loss. Thus, a dual role of microglia complicates the microglial contribution to neurodegeneration. In the present studies, we investigated the role of microglia in retinal neurodegenerative disorders.

We first studied the role of microglial activation in retinitis pigmentosa (RP), an inherited photoreceptor-degenerative disease. In some RP patients, rod-specific genetic mutations lead to rod degeneration followed by cone death. It has been previously shown that microglia respond to pathological disruptions and become activated in RP. However, the role of microglial activation in RP remains elusive. In this study, we investigated the contribution of microglial activation to photoreceptor degeneration in the rd10 mouse model of RP. First, we found microglial activation was an early event prior to photoreceptor death in RP retinas. Pharmacological suppression of microglial activation by minocycline ameliorated photoreceptor degeneration preserved photoreceptor structure and improved retinal function and visual behavior in the rd10 mouse. Second, we determined that the neuroprotective effects of minocycline were exerted via both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency enhanced microglial neurotoxicity and subsequently accelerated photoreceptor loss in rd10 mice, suggesting that the fractalkine/Cx3cr1 signaling pathway might protect microglial from activation. Collectively, we concluded that suppression of microglial activation could be a potential therapeutic approach to the treatment of human RP.

Microglia respond to neural insults by rapidly changing their phenotype and contributing to inflammation. However, the origin of activated microglia in the CNS is hotly debated. In the other study, we investigated the origin of activated microglia in the optic nerve transection (ONT) model. The ONT induces the retrograde degeneration of retinal ganglion cells (RGCs). In response to RGC degeneration, retinal microglia were activated and exhibited a rod microglia phenotype, which displayed sausage-shaped cell bodies and slender processes and aligned parallelly with the axon bundles of RGCs. We first characterized temporal and spatial appearances of rod microglia in the ONT model. We found that rod microglia were capable of phagocytosing RGC debris. Moreover, we found that retinal resident microglia rather than bone-marrow-derived precursors were the major contributor to microgliosis. Collectively, this study sheds light on the function and origin of activated microglia in neurodegeneration, which may facilitate therapeutic interventions aiming at restraining the neuroinflammation in neurodegenerative disorders.