From compliment to insult: genetics of the complement system in physiology and disease in the human retina

Mullins, Robert F.; Warwick, Alasdair; Sohn, Elliott H.; Lotery, Andrew

doi:10.1093/hmg/ddx181

Cited by 16 publications

(12 citation statements)

References 81 publications

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“…As a result of studies associating increased complement activation with retinal degeneration and implicating complement-related genes as conferring genetic risks of age-related macular degeneration (AMD) (15,65), there is much current interest in strategies to inhibit complement activation as a treatment for degenerative retinal diseases (66)…”

Section: Discussionmentioning

confidence: 99%

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

Silverman

Wang

et al. 2018

Preprint

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One Sentence Summary:Complement activation mediates adaptive neuroprotection for photoreceptors by facilitating C3-CR3 dependent microglial clearance of apoptotic cells. Abstract:Complement activation has been implicated as an inflammatory driver of neurodegeneration in retinal and brain pathologies. However, its involvement and influence of photoreceptor degeneration in retinitis pigmentosa (RP), an inherited, largely incurable blinding disease, is unclear. We discover that markedly upregulated retinal expression of multiple complement components coincided spatiotemporally with photoreceptor degeneration in both the rd10 mouse model and in human specimens of RP, with increased complement C3 expression and activation localizing to infiltrating microglia near photoreceptors. Genetic ablation of C3 in the rd10 background resulted in accelerated structural and functional photoreceptor degeneration and altered retinal expression of inflammatory genes. These effects were phenocopied by the genetic deletion of CR3, a microglia-expressed receptor for the C3 activation product C3b, implicating an adaptive microglial-mediation mechanism involving C3-CR3 interaction. Deficiency of either C3 or CR3 resulted in deficient microglial phagocytosis of apoptotic photoreceptors in vivo, as well as increased microglial neurotoxicity to photoreceptors in vitro. These findings demonstrate a novel adaptive role for complement activation in RP that facilitates microglial clearance of apoptotic photoreceptors, without which increased proinflammatory microglial neurotoxicity ensues. These positive contributions of complement via microglial-mediated mechanisms are important in the design of immunomodulatory therapeutic approaches to neurodegeneration.

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Section: Discussionmentioning

confidence: 99%

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

Silverman

Wang

et al. 2018

Preprint

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“…The variant increases the risk for AMD 4.6-fold in individuals heterozygous for the haplotype and 7.4-fold in individuals homozygous as it appears to reduce the ability of CRP to inhibit AP complement activation [36]. C3 has been shown to result in reduced binding to CFH and reduced complement regulation leading to increased membrane attack complex (MAC) deposition at the choriocapillaris [37,38]. The association of AMD pathogenesis with chromosome 10q26, which surrounds ARMS2 and HTRA1, has also been demonstrated in many studies although the debate is ongoing as to the causal allele and underlying pathogenic mechanism [39].…”

Section: Amd Pathogenic Mechanisms and Interaction Of Genetic/environmentioning

confidence: 99%

Epigenetics in age-related macular degeneration: new discoveries and future perspectives

Gemenetzi

Lotery

2020

Cell. Mol. Life Sci.

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“…Second, the cells that survive complement attack adopt an angiogenic phenotype ( 25 ). While complement activation and MAC accumulation in the choriocapillaris in AMD are well-established events ( 26 ), the precise details for how and why these events occur remain to be fully elucidated.…”

Section: The Complement System In Amdmentioning

confidence: 99%

C-Reactive Protein As a Mediator of Complement Activation and Inflammatory Signaling in Age-Related Macular Degeneration

Chirco

Potempa

2018

Front. Immunol.

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Age-related macular degeneration (AMD) is a devastating neurodegenerative disease affecting millions worldwide. Complement activation, inflammation, and the loss of choroidal endothelial cells have been established as key factors in both normal aging and AMD; however, the exact mechanisms for these events have yet to be fully uncovered. Herein, we provide evidence that the prototypic acute phase reactant, C-reactive protein (CRP), contributes to AMD pathogenesis. We discuss serum CRP levels as a risk factor for disease, immunolocalization of distinct forms of CRP in the at-risk and diseased retina, and direct effects of CRP on ocular tissue. Furthermore, we discuss the complement system as it relates to AMD pathophysiology, provide a model for the role of CRP in this disease, and outline current therapies being developed and tested to treat AMD patients.

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From compliment to insult: genetics of the complement system in physiology and disease in the human retina

Cited by 16 publications

References 81 publications

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

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

Epigenetics in age-related macular degeneration: new discoveries and future perspectives

C-Reactive Protein As a Mediator of Complement Activation and Inflammatory Signaling in Age-Related Macular Degeneration

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