Complement Factor C3a Alters Proteasome Function in Human RPE Cells and in an Animal Model of Age-Related RPE Degeneration

Carvalho, J. Emanuel Ramos de; Klaassen, Ingeborg; Vogels, I. M. C.; Schipper-Krom, Sabine; Noorden, C. J. F. Van; Reits, Eric; Gorgels, Theo G. M. F.; Bergen, Arthur A. B.; Schlingemann, Reinier O.

doi:10.1167/iovs.13-12374

Cited by 29 publications

(38 citation statements)

References 64 publications

(71 reference statements)

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“…The underlying mechanisms are not entirely clear, but seem to include a combined effect on reduced cell turnover and autophagy, altered redox balance, and insulin responsiveness (161, 162). Complement is at the nexus of these processes, and several topical studies indeed suggest direct links between complement and aging: C3a downregulates proteasome activity (which is essential to normal protein turnover) in human pigment epithelial cells from older individuals, thereby connecting the complement system with intracellular protein longevity (163); C1q levels increase with age and C1q-mediated activation of canonical wnt signaling—which has been implicated in mammalian aging—promotes age-associated decline in tissue regeneration in mice (164), and C3aR and C5aR activation may regulate telomerase activity and preservation of telomer length in cardiac-resident stem cells (165). Against this background, it will be exciting to now (re)explore the full range of the “powers of this unexpected force from within the cell.”…”

Section: Early Coevolution Of Complement and Metabolismmentioning

confidence: 99%

Keeping It All Going—Complement Meets Metabolism

Kolev

Kemper²

2017

Front. Immunol.

380

553

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The complement system is an evolutionary old and crucial component of innate immunity, which is key to the detection and removal of invading pathogens. It was initially discovered as a liver-derived sentinel system circulating in serum, the lymph, and interstitial fluids that mediate the opsonization and lytic killing of bacteria, fungi, and viruses and the initiation of the general inflammatory responses. Although work performed specifically in the last five decades identified complement also as a critical instructor of adaptive immunity—indicating that complement’s function is likely broader than initially anticipated—the dominant opinion among researchers and clinicians was that the key complement functions were in principle defined. However, there is now a growing realization that complement activity goes well beyond “classic” immune functions and that this system is also required for normal (neuronal) development and activity and general cell and tissue integrity and homeostasis. Furthermore, the recent discovery that complement activation is not confined to the extracellular space but occurs within cells led to the surprising understanding that complement is involved in the regulation of basic processes of the cell, particularly those of metabolic nature—mostly via novel crosstalks between complement and intracellular sensor, and effector, pathways that had been overlooked because of their spatial separation. These paradigm shifts in the field led to a renaissance in complement research and provide new platforms to now better understand the molecular pathways underlying the wide-reaching effects of complement functions in immunity and beyond. In this review, we will cover the current knowledge about complement’s emerging relationship with the cellular metabolism machinery with a focus on the functional differences between serum-circulating versus intracellularly active complement during normal cell survival and induction of effector functions. We will also discuss how taking a closer look into the evolution of key complement components not only made the functional connection between complement and metabolism rather “predictable” but how it may also give clues for the discovery of additional roles for complement in basic cellular processes.

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Section: Early Coevolution Of Complement and Metabolismmentioning

confidence: 99%

Keeping It All Going—Complement Meets Metabolism

Kolev

Kemper²

2017

Front. Immunol.

380

553

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“…Notably, in the RPE, the activity of β 5 is the rate-limiting step of proteasome activity [20,27,65]. Changes due to nano-curcumin treatment approximate those in other conditions that have been shown to be associated with β 5 proteasome activity inhibition, namely, aging [63] and complement overactivation [73]. Changes in the ratio between the immunoproteasome and the classic proteasome are indicative of cellular stress, inflammation, and oxidative stress [24-26, 60, 73].…”

Section: Discussionmentioning

confidence: 99%

Modulation of the Proteasome Pathway by Nano-Curcumin and Curcumin in Retinal Pigment Epithelial Cells

Carvalho¹,

Verwoert²,

Vogels³

et al. 2017

Ophthalmic Res

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Introduction: Curcumin has multiple biological effects including the modulation of protein homeostasis by the ubiquitin-proteasome system. The purpose of this study was to assess the in vitro cytotoxic and oxidative effects of nano-curcumin and standard curcumin and characterize their effects on proteasome regulation in retinal pigment epithelial (RPE) cells. Methods: Viability, cell cycle progression, and reactive oxygen species (ROS) production were determined after treatment with nano-curcumin or curcumin. Subsequently, the effects of nano-curcumin and curcumin on proteasome activity and the gene and protein expression of proteasome subunits PA28α, α₇, β₅, and β_5i were assessed. Results: Nano-curcumin (5-100 μM) did not show significant cytotoxicity or anti-oxidative effects against H₂O₂-induced oxidative stress, whereas curcumin (≥10 μM) was cytotoxic and a potent inducer of ROS production. Both nano-curcumin and curcumin induced changes in proteasome-mediated proteolytic activity characterized by increased activity of the proteasome subunits β₂ and β_5i/β₁ and reduced activity of β₅/β_1i. Likewise, nano-curcumin and curcumin affected mRNA and protein levels of household and immunoproteasome subunits. Conclusions: Nano-curcumin is less toxic to RPE cells and less prone to induce ROS production than curcumin. Both nano-curcumin and curcumin increase proteasome-mediated proteolytic activity. These results suggest that nano-curcumin may be regarded as a proteasome-modulating agent of limited cytotoxicity for RPE cells.

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“…Whole-blood RNA was extracted using the PAXgene blood RNA kit, including treatment with DNase I to prevent genomic DNA contamination, strictly following the manufacturer's instructions (Qiagen). Total RNA was isolated from dissected retinas (pooled from 3 nondiabetic eyes) and human donor RPE cells 16 (pooled from 5 nondiabetic eyes) in TRIzol reagent (Life Technologies, Carlsbad, CA, USA) following the manufacturer's instructions. Total RNA was dissolved in 50 lL of RNase-free water and measured using a NanoDrop instrument (model ND1000 spectrophotometer; NanoDrop Technologies, Wilmington, DE, USA).…”

Section: Sample Collection and Rna Isolationmentioning

confidence: 99%

Association of Circulating Markers With Outcome Parameters in the Bevacizumab and Ranibizumab in Diabetic Macular Edema Trial

Fickweiler

Klaassen

Vogels

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to evaluate selected candidate biomarkers as potential markers for patients with diabetic macular edema (DME) who receive antivascular endothelial growth factor (VEGF) therapy METHODS. Selected biomarkers included blood levels of messenger RNA (mRNA) of retinoschisin, RPE65, rhodopsin, and endothelial progenitor cell markers CD34 and CD133. Blood samples were obtained from 89 patients with DME according to the study protocol of the Bevacizumab and Ranibizumab in Diabetic Macular Edema (BRDME) study. During each monthly visit, patients underwent optical coherence tomography scanning and visual acuity was measured. Anti-VEGF injections were administered at fixed monthly intervals over 6 months. Analyses of covariance using simplified and linear mixed models were used to examine the correlations between candidate markers and changes in visual acuity and central subfield thickness.RESULTS. Plasma mRNA levels of retinoschisin were negatively associated with visual acuity, and plasma mRNA levels of rhodopsin were positively associated with visual acuity in patients with DME (P < 0.01 and P < 0.05, respectively). In addition, changes in central subfield thickness between baseline and months 1, 2, and 3 during anti-VEGF treatment were associated with mRNA levels of retinoschisin, rhodopsin, and the ratio of retinoschisin-torhodopsin (P < 0.01, all).CONCLUSIONS. This prospective, multicenter study found that circulating mRNA levels of retinoschisin and rhodopsin are associated with visual acuity and changes in central subfield thickness during anti-VEGF therapy in patients with DME. (ClinicalTrials.gov number: NCT01635790.)

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Complement Factor C3a Alters Proteasome Function in Human RPE Cells and in an Animal Model of Age-Related RPE Degeneration

Cited by 29 publications

References 64 publications

Keeping It All Going—Complement Meets Metabolism

Keeping It All Going—Complement Meets Metabolism

Modulation of the Proteasome Pathway by Nano-Curcumin and Curcumin in Retinal Pigment Epithelial Cells

Association of Circulating Markers With Outcome Parameters in the Bevacizumab and Ranibizumab in Diabetic Macular Edema Trial

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