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.

Suppression of microglial activation is neuroprotective in a mouse model of human retinitis pigmentosa

Retinal cell survival requires an equilibrium between oxygen, reactive oxygen species, and antioxidant molecules that counteract oxidative stress damage. Oxidative stress alters cell homeostasis and elicits a protective cell response, which is most relevant in photoreceptors and retinal ganglion cells, neurons with a high metabolic rate that are continuously subject to light/oxidative stress insults. We analyze how the alteration of cellular endogenous pathways for protection against oxidative stress leads to retinal dysfunction in prevalent (age-related macular degeneration, glaucoma) as well as in rare genetic visual disorders (Retinitis pigmentosa, Leber hereditary optic neuropathy). We also highlight some of the key molecular actors and discuss potential therapies using antioxidants agents, modulators of gene expression and inducers of cytoprotective signaling pathways to treat damaging oxidative stress effects and ameliorate severe phenotypic symptoms in multifactorial and rare retinal dystrophies.

The Relevance of Oxidative Stress in the Pathogenesis and Therapy of Retinal Dystrophies.

Retinitis pigmentosa (RP) is the most common cause of inherited blindness and is characterised by the progressive loss of retinal photoreceptors. However, RP is a highly heterogeneous disease and, while much progress has been made in developing gene replacement and gene editing treatments for RP, it is also necessary to develop treatments that are applicable to all causative mutations. Further understanding of the mechanisms leading to photoreceptor death is essential for the development of these treatments. Recent work has therefore focused on the role of apoptotic and non-apoptotic cell death pathways in RP and the various mechanisms that trigger these pathways in degenerating photoreceptors. In particular, several recent studies have begun to elucidate the role of microglia and innate immune response in the progression of RP. Here, we discuss some of the recent progress in understanding mechanisms of rod and cone photoreceptor death in RP and summarise recent clinical trials targeting these pathways.

https://www.mdpi.com/2073-4425/11/10/1120/pdf

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

VEGFR1 signaling in retinal angiogenesis and microinflammation

This work was supported by Foundation for Science and Technology (FCT), Portugal (Fellowships PD/BD/114115/2015 and PD/BD/127821/2016, Grant PTDC/NEU-OSD/3123/2014 and Strategic Projects UID/NEU/04539/2013, UID/NEU/04539/2019, UIDP/04539/2020 and UIDB/04539/2020), FEDER-COMPETE POCI-01-0145-FEDER-016849, FCOMP-01-0124-FEDER-028417, POCI-01-0145-FEDER-007440) and Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000008: BrainHealth 2020). Grupos UPV/EHU GIU18/50, PUE 2018-04 and ELKARTEK KK-2019/00086 to E.V.

/pdf/neuroprotective-strategies-for-retinal-ganglion-cell-2awiiqvxdm.pdf

Neuroprotective Strategies for Retinal Ganglion Cell Degeneration: Current Status and Challenges Ahead

The retina is a complex tissue with multiple cell layers that are highly ordered. Its sophisticated structure makes it especially sensitive to external or internal perturbations that exceed the homeostatic range. This necessitates the continuous surveillance of the retina for the detection of noxious stimuli. This task is mainly performed by microglia cells, the resident tissue macrophages which confer neuroprotection against transient pathophysiological insults. However, under sustained pathological stimuli, microglial inflammatory responses become dysregulated, often worsening disease pathology. In this review, we provide an overview of recent studies that depict microglial responses in diverse retinal pathologies that have degeneration and chronic immune reactions as key pathophysiological components. We also discuss innovative immunomodulatory therapy strategies that dampen the detrimental immunological responses to improve disease outcome.

/pdf/microglia-in-retinal-degeneration-r7pgcemwt0.pdf

Microglia in Retinal Degeneration.

Genetic variants of high-temperature requirement A serine peptidase 1 (HTRA1) and age-related maculopathy susceptibility 2 (ARMS2) are associated with age-related macular degeneration (AMD). One HTRA1 single nucleotide polymorphism (SNP) is situated in the promotor region (rs11200638) resulting in increased expression, while two synonymous SNPs are located in exon 1 (rs1049331:C > T, rs2293870:G > T). HtrA1 is known to inhibit transforming growth factor-β (TGF-β) signaling, a pathway regulating quiescence of microglia, the resident immune cells of the brain and retina. Microglia-mediated immune responses contribute to AMD pathogenesis. It is currently unclear whether AMD-associated HTRA1 variants influence TGF-β signaling and microglia phenotypes. Here, we show that an HtrA1 isoform carrying AMD-associated SNPs in exon 1 exhibits increased proteolytic activity. However, when incubating TGF-β-treated reactive microglia with HtrA1 protein variants, neither the wildtype nor the SNP-associated isoforms changed microglia activation in vitro.

Isha Akhtar-Schaefer

Papers

Microglia in Retinal Degeneration.

AMD-Associated HTRA1 Variants Do Not Influence TGF-β Signaling in Microglia.