Suppression of Microglial Activation Is Neuroprotective in a Mouse Model of Human Retinitis Pigmentosa

Abstract

Retinitis pigmentosa (RP) is a photoreceptor-degenerative disease caused by various mutations and is characterized by death of rod photoreceptor cell followed by gradual death of cone photoreceptors. The molecular mechanisms that lead to rod and cone death are not yet fully understood. Neuroinflammation contributes to the progression of many chronic neurodegenerative disorders. However, it remains to be determined how microglia contribute to photoreceptor disruption in RP. In this study, we explored the role of microglia as a contributor to photoreceptor degeneration in the rd10 mouse model of RP. First, we demonstrated that microglia activation was an early alteration in RP retinas. Inhibition of microglia activation by minocycline reduced photoreceptor apoptosis and significantly improved retinal structure and function and visual behavior in rd10 mice. Second, we identified that minocycline exerted its neuroprotective effects through both anti-inflammatory and anti-apoptotic mechanisms. Third, we found that Cx3cr1 deficiency dysregulated microglia activation and subsequently resulted in increased photoreceptor vulnerability in rd10 mice, suggesting that the Cx3cl1/Cx3cr1 signaling pathway might protect against microglia neurotoxicity. We concluded that suppression of neuroinflammatory responses could be a potential treatment strategy aimed at improving photoreceptor survival in human RP.

MUTYH promotes oxidative microglial activation and inherited retinal degeneration

“…Previous studies showed that microglial cells infiltrate into the ONL concomitantly or before the onset of photoreceptor cell death in animal models of RP (32). In the present investigation, the double immunostaining for 8-oxoG and Iba-1 revealed that part of the 8-oxoG signal was colocalized with that of Iba-1 in both the rd10;Mutyh +/+ and rd10;Mutyh −/− mice at P17 ( Figure 4A).…”

“…We recently reported that the ocular inflammatory levels of RP patients are negatively correlated with visual function (36,37). In animal models of RP, it was shown that microglia migrate into the ONL at the onset of or before photoreceptor cell death (10,38), and the suppression of microglial activation ameliorates photoreceptor cell loss (32). However, the mechanisms underlying microglial activation in RP have not been fully elucidated.…”

Halting progressive neurodegeneration in advanced retinitis pigmentosa

“…First, our direct rescue of rods reduced the level of cell death in the RP retinae, which may lead to an increase in positive trophic factors (39) and a decrease in toxic factors. For example, we demonstrated that gene therapy reverses Müller glial cell activation ( Figure 5 and Supplemental Figure 2), which, by itself, is likely to exert a positive impact on cell survival (40).…”

Alterations to retinal architecture prior to photoreceptor loss in a mouse model of retinitis pigmentosa

“…This could lead to oxidative stress in the ONL (Zeng et al, 2014) and subsequent apoptosis (Carmody and Cotter 2000;Carmody et al, 1999), as photoreceptors are highly sensitive to changes in oxygen levels (Wellard et al, 2005). In support of this, anti-oxidants and antiinflammatories have been shown to slow photoreceptor cell death in rd10 mice (Komeima et al, 2007;Peng et al, 2014). Future studies will therefore be aimed at further understanding the role that microglia play in the course of degeneration in the rd10 retina.…”

“…In the rd10 mouse it has recently been shown that depleting microglia as well as inhibiting microglial phagocytosis resulted in increased protection of mutated photoreceptors (Zhao et al, 2015). It has also been shown in other mouse models of RP that NADPH oxidase activation in microglia resulted in rod cell death (Zeng et al, 2014) and inhibition of reactive gliosis prevents apoptosis of retinal neurons and provides neuroprotection (Ganesh and Chintala 2011;Peng et al, 2014). Interestingly, we also know that increased levels of reactive oxygen species are found in the ONL of rd10 retinas (Bhatt et al, 2010), potentially due to activated microglia.…”