Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Akhtar-Schäfer, Isha; Wang, Luping; Krohne, Tim U.; Xu, Heping; Langmann, Thomas

doi:10.15252/emmm.201708259

Cited by 101 publications

(78 citation statements)

References 379 publications

(482 reference statements)

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“…Innate immunity is considered the immediate immune response to an insult or pathogen. The retina is equipped with a highly sensitive innate immune system that responds with three key pathways: migration of microglia cells, activation of the complement system to opsonize cellular debris, and inflammasome assembly in the RPE (reviewed in [20]). To achieve this coordinated response, retinal cells express a panoply of immune protein receptors and mediators such as, microbial sensors (Toll-like receptors-TLRs), NOD-like receptors-NLRs, RIG-1 like helicases), cytokines, chemokines, as well as a group of complement components; all directed to assist the cells with eliminating the current insult [21].…”

Section: Inflammation and Gliosismentioning

confidence: 99%

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

2020

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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.

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Section: Inflammation and Gliosismentioning

confidence: 99%

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

2020

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“…Age-related macular degeneration (AMD) is a complex disease with many risk factors contributing to its pathogenesis (2)(3)(4). Despite the fact that clinical and genetic data support an association of a chronic, low-grade inflammatory response in the outer retina during the development of AMD, the exact underlying mechanisms and triggers of inflammation remain elusive (5).…”

Section: Introductionmentioning

confidence: 99%

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

et al. 2020

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Granzymes are a family of serine proteases first shown to be intracellular initiators of immune-mediated cell death in target pathogenic cells. In addition to its intracellular role, Granzyme B (GzmB) has important extracellular functions in immune regulation and extracellular matrix (ECM) degradation. Verified substrates of extracellular GzmB activity include tight junctional and ECM proteins. Interestingly, little is known about the activity of GzmB in the outer human retina, a tissue in which the degradation of the tight junctional contacts of retinal pigment epithelial (RPE) cells and within the external limiting membrane, as well as remodeling of the ECM in Bruch's membrane, cause the breakdown of the blood-retinal barrier and slowing of metabolite transport between neuroretina and choroidal blood supply. Such pathological changes in outer retina signal early events in the development of age-related macular degeneration (AMD), a multifactorial, chronic inflammatory eye disease. This study is the first to focus on the distribution of GzmB in the outer retina of the healthy and diseased post-mortem human eye. Our results revealed that GzmB is present in RPE and choroidal mast cells. More immunoreactive cells are present in older (>65 years) compared to younger (<55 years) donor eyes, and choroidal immunoreactive cells are more numerous in eyes with choroidal neovascularization (CNV), while RPE immunoreactive cells are more numerous in eyes with soft drusen, an early AMD event. In vitro studies demonstrated that RPE-derived tight junctional and ECM proteins are cleaved by exogenous GzmB stimulation. These results suggest that the increased presence of GzmB immunoreactive cells in outer retina of older (healthy) eyes as well as in diseased eyes with CNV (from AMD) and eyes with soft drusen exacerbate ECM remodeling in the Bruch's membrane and degradation of the blood-retinal barrier. Currently there are no treatments that prevent remodeling of the Bruch's membrane and/or the loss of function of the outer blood-retinal barrier, Matsubara et al. Granzyme B in Outer Retina known to promote early AMD changes, such as drusen deposition, RPE dysfunction and pro-inflammation. Specific inhibitors of GzmB, already in preclinical studies for non-ocular diseases, may provide new strategies to stop these early events associated with the development of AMD.

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“…Parkinson's disease (9), age-related macular degeneration (AMD) (10)(11)(12), diabetic retinopathy (13,14), inherited retinal degeneration (15) and glaucoma (16). Targeting microglial activation is considered to be an effective approach for the management of neurodegenerative diseases (17)(18)(19). Until now, the attempts to control microglial activation with general immune suppression (steroids or immune suppressive drugs) have achieved limited clinical success (20)(21)(22).…”

Section: Introductionmentioning

confidence: 99%

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

Peñalva

Little

et al. 2020

Preprint

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BackgroundWe generated a mouse model of primary microglial dysfunction by deleting two negative immune regulatory genes, Cx3cr1 and Socs3 (in LysM+ cells). This study aimed to understand how primary microglial dysfunction impacts retinal neurons during aging.MethodsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp double knockout (DKO), LysMCre-Socs3fl/fl, Cx3cr1gfp/gfp and Socs3fl/fl mice were maintained up to 12 months. Eyes were collected and processed for immunohistochemistry of IBA-1, cone arrestin, secretagogin, PKCα and GABA. Brain microglia from DKO and WT mice were stimulated with LPS + IFNγ or IL4. The expression of TNFα, IL1β, IL6, iNOS, IL12p40, IL23p19, CCL2, CCL5, CXCL2, IL10, CD206 and Arg1 were examined by real-time RT-PCR and protein production was measured by Luminex assay. Retinal explants from C57BL/6J mice were co-cultured with microglia from DKO or WT mice for 24 h, after which the number of cone arrestin+ cells in retinal flatmount were quantified.ResultsIn 3–5 month old mice, the number of microglia in retinal ganglion cell layer (GCL) and inner plexiform layer (IPL) were comparable in all strains. The DKO mice had a significantly higher number of microglia in the outer plexiform layer (OPL) but significantly lower numbers of cone arrestin+, secretagogin+ and GABA+ cells compared to Socs3fl/fl and single KO mice. During aging, 57% of the DKO mice died before 12 months old. The 10–12 months old DKO mice had significantly highers number of microglia in GCL/IPL and OPL than age-matched Socs3fl/fl and single KO mice. The aged DKO mice developed retinal pigment epithelial (RPE) dysmorphology accompanied by subretinal microglial accumulation. The number of photoreceptors, bipolar cells (Secretagogin+ or PKCα+) and GABA+ amacrine cells was significantly lower in aged DKO mice compared to age-matched Socs3fl/fl and single KO mice. Microglia from DKO mice showed significantly higher levels of phagocytic activity and produced higher levels of TNFα, IL6, CCL2, CCL5, CXCL2 and CXCL10 compared to microglia from Socs3fl/fl mice. Co-culture of retinal explants with DKO microglia (pre-treated with LPS + IFNγ or IL4) significantly reduced cone photoreceptor survival.ConclusionsThe LysMCre-Socs3fl/flCx3cr1gfp/gfp DKO mice displayed primary microglial dysfunction and developed age-related retinal microgliopathy characterized by aggragated microglial activation and multiple retinal neuronal and RPE degeneration.Trial registration: Not applicable. The article does not contain any results from human participants.

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Modulation of three key innate immune pathways for the most common retinal degenerative diseases

Cited by 101 publications

References 379 publications

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

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

Retinal Distribution and Extracellular Activity of Granzyme B: A Serine Protease That Degrades Retinal Pigment Epithelial Tight Junctions and Extracellular Matrix Proteins

Deletion of Socs3 in LysM+ Cells and Cx3cr1 Resulted in Age-dependent Development of Retinal Microgliopathy

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