C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Silverman, Sean; Ma, Wenxin; Wang, Xu; Zhao, Lian; Wong, Wai T.

doi:10.1084/jem.20190009

Cited by 84 publications

(72 citation statements)

References 71 publications

(99 reference statements)

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“…The introduction of cytokines IL-6, IFNγ or TNFα to microglial cultures promotes the synthesis of complement components [ 122 ]. Increased C3 expression was observed in infiltrating microglia in the outer nuclear layer of rd10 mice along with opsonisation of degenerating photoreceptors by C3b [ 124 ]. Interestingly, this study also showed that genetic ablation of C3 or the C3 receptor (CR3) accelerated photoreceptor degeneration.…”

Section: Recruitment and Activation Of Microglia And Monocytesmentioning

confidence: 99%

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

146

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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.

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Section: Recruitment and Activation Of Microglia And Monocytesmentioning

confidence: 99%

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Newton

Megaw

2020

Genes

146

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“…In our comprehensive analyses, we furthermore detected a considerable number of genes encoding for components of the complement system that is part of the innate immune system. Various complement factors have been reported to be upregulated in retinae of human patients suffering from RP or in retinae of mice following genetically or light-induced photoreceptor degeneration in mice (47)(48)(49)(51)(52)(53)(54). Activation of the complement system promotes microglia/in ltrative macrophages migration and eventually complement activated lysis (48,51).…”

Section: Discussionmentioning

confidence: 99%

“…Still, con icting data exist regarding the exact role of complement system activation and its impact on photoreceptor degeneration. Mice with a de ciency in complement factor D are protected from light-induced photoreceptor degeneration (47), indicating a detrimental role for photoreceptor survival, but the de ciency in complement component 3 (C3) or complement receptor 3 (CR3) in a genetic mouse model of photoreceptor degeneration increases microglia-mediated neurotoxicity to photoreceptors (54). Thus, the detailed function of the complement system and its speci c role in microglia and Müller cells and its contribution to photoreceptor degeneration has yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

Retinitis Pigmentosa Results in Neurodegeneration Concomitant With Neuroinflammation, Extracellular Matrix Disorganization and the Upregulation of Neuroprotective Pathways in Glial Cells and Neurons

Bielmeier¹,

Roth²,

Schmitt³

et al. 2020

Preprint

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BackgroundHereditary retinal degenerations like retinitis pigmentosa (RP) are amongst the leading causes of blindness in younger patients. To enable in vivo investigation of cellular and molecular mechanisms responsible for photoreceptor cell death and to allow testing of therapeutic strategies that could prevent retinal degeneration, animal models have been created. Here, we in-depth characterized the transgenic VPP mouse model, a genetic model for autosomal dominant RP. MethodsWe examined the degree of photoreceptor degeneration and studied the impact of the VPP transgene-induced retinal degeneration on the transcriptome level of the retina using next generation RNA sequencing (RNASeq) analyses followed by weighted correlation network analysis (WGCNA). We furthermore identified cellular subpopulations responsible for some of the observed dysregulations using in situ hybridizations, immunofluorescent staining and 3D reconstruction. ResultsOne month-old VPP mice showed a significantly higher number of apoptotic photoreceptor cells that resulted in a significantly thinner ONL in three months-old VPP mice, concomitant with an increase in reactivity of microglia and Müller cells. By RNASeq analysis we identified 9,256 dysregulated genes and six significantly associated gene modules in the subsequently performed WGCNA. Gene ontology enrichment showed, amongst others, dysregulation of TGF-β regulated extracellular matrix organization, factors of the (ocular) immune system/response and apoptosis. ConclusionThe predominant effect pointed towards induction of neuroinflammation and the upregulation of neuroprotective pathways like TGF-β, G-protein activated and VEGF signaling that were significantly associated with the VPP transgene-induced photoreceptor degeneration. Thus, modulation of these processes might represent new therapeutic options to delay the degeneration of photoreceptors in diseases like RP.

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“…Rather, dying or stressed photoreceptors were the object of phagocytosis, in a manner mediated by complement component 3 (C3) and its receptor CR3. 32 Moreover, inhibition of microglia phagocytosis was associated with preservation of rod photoreceptors. 31 In summary, over the last 15 years, there has been a dramatic increase in our knowledge of the role of microglia in regulating normal health of the nervous system including the retina.…”

Section: Resident Microglia As Guardians Of the Retinamentioning

confidence: 99%

“…TUNEL positive photoreceptors). Rather, dying or stressed photoreceptors were the object of phagocytosis, in a manner mediated by complement component 3 (C3) and its receptor CR3 . Moreover, inhibition of microglia phagocytosis was associated with preservation of rod photoreceptors …”

Section: Resident Microglia As Guardians Of the Retinamentioning

confidence: 99%

Contribution of microglia and monocytes to the development and progression of age related macular degeneration

Fletcher

2020

Ophthalmic Physiologic Optic

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Purpose Age related macular degeneration (AMD) is the leading cause of irreversible vision loss in industrialised nations. Based on genetics, as well as proteome analysis of drusen, the role the innate immune system in the development and/or progression of the disease is well established. Mononuclear phagocytes, such as microglia and monocytes, play critical roles in innate immunity. Here, the role of retinal microglia in mediating normal retinal function, and how these cells change with age is discussed, so as to understand their role in the development and progression of AMD. Recent findings It is now known that microglia dynamically survey the neural environment, responding rapidly to even the most subtle neural injury. The dynamic and phagocytic roles of microglia can change with age contributing to alteration in the response of these cells to damage with age. Accumulation of innate immune cells in the subretinal space is a hallmark feature of the development of AMD, reflecting either an increase in migration of monocytes into the retina, or a failure of immune cell elimination from the retina. Furthermore, changes in phagocytic ability of immune cells could contribute to the accumulation of drusen deposits in the posterior eye. Summary An overview of how retinal microglia maintain retinal homeostasis under normal conditions is provided, and then how they contribute to each stage of AMD. In addition, circulating monocytes are altered in those with AMD, contributing to the overall inflammatory state. Understanding the role of cells of the innate immune system in AMD may uncover novel therapeutic targets with which to reduce either the development or progression of disease.

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C3- and CR3-dependent microglial clearance protects photoreceptors in retinitis pigmentosa

Cited by 84 publications

References 71 publications

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Mechanisms of Photoreceptor Death in Retinitis Pigmentosa

Retinitis Pigmentosa Results in Neurodegeneration Concomitant With Neuroinflammation, Extracellular Matrix Disorganization and the Upregulation of Neuroprotective Pathways in Glial Cells and Neurons

Contribution of microglia and monocytes to the development and progression of age related macular degeneration

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