Compliments of Factor H: What’s in it for AMD?

Mattapallil, Mary J.; Caspi, Rachel R

doi:10.1016/j.immuni.2017.02.008

Cited by 11 publications

(8 citation statements)

References 9 publications

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“…It is possible that inhibitory CRegs play an important role during tissue repair in the eye, limiting complement-mediated vascular injury. Intriguingly, several of these CRegs are encoded by genes associated with age-related macular degeneration (AMD) (35,36); for example, AMD susceptibility allele ARMD1 encodes Cfhr1/3 (37), ARMD4 encodes Cfh (38)(39)(40)(41), ARMD13 encodes Cfi (35), and ARMD14 encodes Cfb (42) (Fig. 4C).…”

Section: Discussionmentioning

confidence: 99%

Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry

Liu

Thomson

Khalatyan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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The blood-aqueous barrier plays a key role in regulating aqueous humor homeostasis by selectively restricting passage of proteins into the eye. The kinetics of aqueous flow are traditionally measured using artificial markers; however, these marker molecules do not address the barrier's selective permeability to plasma proteins. Here we applied stable isotope labeling of all serum proteins with nitrogen-15 (N) atoms. Following systemic injection of this "heavy" serum in mice, the N-to-endogenous nitrogen-14 (N) ratio of each protein in aqueous was measured by mass spectrometry. By monitoring the kinetic changes in these ratios, we determined the permeability profiles of hundreds of serum proteins. Meanwhile, we subjected one of the eyes to neoangiogenic wound healing by inflicting injury to the corneal limbus and compared the N proteomes between the normal eyes and the recovering eyes at 2 weeks after injury. In the injured eye, we detected markedly enhanced permeability to inhibitory complement regulator proteins, such as Cfh, Cfhr, Cfb, Cfi, Cfd, and Vtn. Many of the proteins in this group are implicated in age-related macular degeneration associated with leakage of the blood-retinal barrier due to inflammation. To rule out the possibility that the observed leakage was due simply to physical damage of the blood vessels, we separately created a neovascularization model using an alkali burn of the avascular cornea. In this latter model, elevated levels of Cfh and Cfb were evident. These findings suggest that ocular neovascularization is associated with enhanced permeability to serum complement regulators.

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Section: Discussionmentioning

confidence: 99%

Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry

Liu

Thomson

Khalatyan

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…Drusen proteomic analysis has demonstrated the presence of multiple proteins, among which TIMP3 [18], clusterin, vitronectin, and serum albumin were the most common proteins in normal donor drusen, whereas crystallins were more frequently present in AMD donor drusen [38,56,57]. Drusen inflammatory and complement proteins, such as beta amyloid [58], immunoglobulin light chains, factor X, and C5 and − 5b, have received special attention [59], specifically since CFH [11] , is the product of impaired phagocytosis of the POS due to decreased RPE lysosomal activity [65]. Physiologically, lipofuscin is degraded completely or exocytosed by the RPE cells basolaterally and removed by the choroidal blood stream [66].…”

Section: Drusen Maculopathymentioning

confidence: 99%

“…Etiologically, AMD is a multifactorial disease. Genetic variants associated with AMD include complement factor (CF)H [11] and CFH-related genes 1 to 5 [12], complement protein (C)3 [13], C9 [14], age-related maculopathy susceptibility (ARMS)2 gene [15], and the vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) axis [16,17]. In addition, other genetic variants have shown a causal link to AMD, such as tissue inhibitor metalloproteinase (TIMP) 3 [18], fibrillin [19], collagen 4A3, and metalloproteinase (MMP) 19 and − 9 [20].…”

Section: Introductionmentioning

confidence: 99%

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

Mammadzada

Corredoira

André

2019

Cell. Mol. Life Sci.

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Understanding the mechanisms that underlie age-related macular degeneration (AMD) has led to the identification of key molecules. Hypoxia-inducible transcription factors (HIFs) have been associated with choroidal neovascularization and the progression of AMD into the neovascular clinical phenotype (nAMD). HIFs regulate the expression of multiple growth factors and cytokines involved in angiogenesis and inflammation, hallmarks of nAMD. This knowledge has propelled the development of a new group of therapeutic strategies focused on gene therapy. The present review provides an update on current gene therapies in ocular angiogenesis, particularly nAMD, from both basic and clinical perspectives.

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“…Similarly, C3 -/and CR3 -/were bred with wild type C57BL6/J animals to generate all three genotypes in the same litter for agematched comparisons. All experimental animals were genotyped by gene sequencing to confirm the absence of the rd8 mutation (70). Both male and female mice in the age range of postnatal days 16 to 35 were used as specified in individual experiments.…”

Section: Experimental Animalsmentioning

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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Compliments of Factor H: What’s in it for AMD?

Cited by 11 publications

References 9 publications

Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry

Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

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

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Compliments of Factor H: What’s in it for AMD?

Cited by 11 publications

References 9 publications

Selective permeability of mouse blood-aqueous barrier as determined by 15 N-heavy isotope tracing and mass spectrometry

Selective permeability of mouse blood-aqueous barrier as determined by 15 N-heavy isotope tracing and mass spectrometry

The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective

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

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Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry

Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵ N-heavy isotope tracing and mass spectrometry