A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes

Alic, Lejla; Papac-Miličević, Nikolina; Rudnick, Ramona B.; Ozsvár-Kozma, Mária; Hartmann, Andrea; Gurbisz, Michael; Hoermann, Gregor; Haslinger-Hutter, Stefanie; Zipfel, Peter F.; Skerka, Christine; Binder, Elisabeth B.; Binder, Christoph J.

doi:10.1073/pnas.1913970117

Cited by 31 publications

(38 citation statements)

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“…Binding of FHR-1 and FHR-5 to cells depends on available receptors and surface ligands; for example, previously we did demonstrate FHR-1 binding to viable neutrophils via the complement receptor CR3 ( 60 ). On necrotic cells, malondialdehyde epitopes represent one of the ligands of FHR-1 and FHR-5, and both FHRs were shown to enhance complement activation when bound to malondialdehyde epitopes in vitro ( 57 , 61 ). The inhibition of FHR-1 and FHR-5 binding to necrotic cells by dNTP and their partial co-localization with DNA suggest that DNA could serve as an additional ligand for both FHRs on necrotic cells ( Supplementary Figure 2 ).…”

Section: Discussionmentioning

confidence: 99%

Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization

et al. 2020

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Complement plays an essential role in the opsonophagocytic clearance of apoptotic/necrotic cells. Dysregulation of this process may lead to inflammatory and autoimmune diseases. Factor H (FH), a major soluble complement inhibitor, binds to dead cells and inhibits excessive complement activation on their surface, preventing lysis, and the release of intracellular material, including DNA. The FH-related (FHR) proteins share common ligands with FH, due to their homology with this complement regulator, but they lack the domains that mediate the complement inhibitory activity of FH. Because their roles in complement regulation is controversial and incompletely understood, we studied the interaction of FHR-1 and FHR-5 with DNA and dead cells and investigated whether they influence the regulatory role of FH and the complement activation on DNA and dead cells. FH, FHR-1, and FHR-5 bound to both plasmid DNA and human genomic DNA, where both FHR proteins inhibited FH–DNA interaction. The FH cofactor activity was inhibited by FHR-1 and FHR-5 due to the reduced binding of FH to DNA in the presence of the FHRs. Both FHRs caused increased complement activation on DNA. FHR-1 and FHR-5 bound to late apoptotic and necrotic cells and recruited monomeric C-reactive protein and pentraxin 3, and vice versa . Interactions of the FHRs with pentraxins resulted in enhanced activation of both the classical and the alternative complement pathways on dead cells when exposed to human serum. Altogether, our results demonstrate that FHR-1 and FHR-5 are competitive inhibitors of FH on DNA; moreover, FHR–pentraxin interactions promote opsonization of dead cells.

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Section: Discussionmentioning

confidence: 99%

Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization

et al. 2020

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“…A polarized monolayer could be detected for untreated and FHR3 treated cells, showing that FHR-3 had no effect on stable cell-cell contacts. We also excluded that ARPE- 19 Due to the number of passages and the slight EMT, which is typical for aged human RPE cells (38), the investigated ARPE-19 cells P38 were termed senescent cells in this study.…”

Section: Resultsmentioning

confidence: 99%

“…Just recently, it was shown that FHR-3 binds to malondialdehyde (MDA)-epitopes (19). These OSE are present on the surface of stressed ARPE-19 cells (16).…”

Section: Resultsmentioning

confidence: 99%

“…OSE can trigger in ammation in the retina, which was inhibited by FH binding (17,18). FHR-1 and FHR-3 also attach to OSE on senescent cells and compete with FH for binding (19). This interference of FHR1 and FHR-3 prevents FH-mediated proteolysis of the central complement component C3 into iC3b and results in enhanced activity of the soluble complement system (20).…”

Section: Introductionmentioning

confidence: 99%

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Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Schäfer

Rasras

Ceteras

et al. 2021

Preprint

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Background Complement Factor H-Related 3 (FHR-3) is a major regulator of the complement system, which is associated with different diseases, such as age-related macular degeneration. The non-canonical local, cellular functions of FHR-3 remained poorly understood.Methods Human retinal pigment epithelium (RPE) cells (ARPE-19 cells and primary human RPE cells (hpRPE)), cultivated in Transwell® inserts, were apically treated with either FHR‑3 alone or with the chimerized monoclonal anti‑FHR-3 antibody RETC-2-ximab, or with FHR-1, FH, Properdin or not treated for 5 – 24 h, respectively. Interaction of FHR-3 with oxidative stress epitopes was determined by ELISA. Internalization studies of FHR-3 or FH by ARPE‑19 cells was determined by immunofluorescence live cell imaging. Impact of FHR-3 on RPE cell-specific complement components and inflammation markers were analyzed on mRNA (RT-qPCR) and on protein level (Western Blot, ELISA, protein secretion assays, immunofluorescence). Results Here, we report that FHR-3 bound to oxidative stress epitopes and competed with FH for interaction. Furthermore, FHR-3 was internalized by senescent viable RPE cells and modulated time-dependently complement component (C3, CFB) and receptor (C3aR, CR3) expression of human RPE cells. Independently of any external blood-derived proteins, complement activation products were detected. Anaphylatoxin C3a was visualized in treated cells and showed a translocation from the cytoplasm to the cell membrane after FHR-3 exposure. Subsequently, FHR-3 induced a RPE cell dependent pro-inflammatory micro-environment. Inflammasome NLRP3 activation and pro-inflammatory cytokine secretion of IL-1ß, IL-18, IL-6 and TNF-α were induced after FHR-3-RPE interaction. Additionally, important pattern recognition molecules of the innate immune system, Toll-like receptors 1 and 3, as well as proteasome subunits were impaired in RPE cells after FHR-3 incubation. A chimerized monoclonal anti-FHR-3 antibody, RETC‑2‑ximab, ameliorated the effect of FHR-3 on ARPE-19 cells.Conclusion Our studies suggest FHR-3 as an exogenous trigger molecule for the RPE cell complosome and as a productive target for a new therapeutic approach using RETC‑2‑ximab for associated degenerative diseases.

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“…Further, we recently demonstrated that genetic deletions of complement factor H-related protein 1 (CFHR1), which was previously shown to bind to MDA-LDL ( 82 ), and 3 (CFHR3) affects the ability of plasma CFH to bind MDA surfaces. Moreover, purified CFHR1 and CFHR3 competes with CFH for binding to MDA-epitopes ( 83 ). Our findings indicate the influence of genetic variations within the CFH/CFHR1/CFHR3 locus on the recognition and binding of OSEs, thereby affecting outcome in diseases associated with oxidative stress and aging such as NAFLD.…”

Section: Introductionmentioning

confidence: 99%

Oxidation-Specific Epitopes in Non-Alcoholic Fatty Liver Disease

Hendrikx

Binder

2020

Front. Endocrinol.

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An improper balance between the production and elimination of intracellular reactive oxygen species causes increased oxidative stress. Consequently, DNA, RNA, proteins, and lipids are irreversibly damaged, leading to molecular modifications that disrupt normal function. In particular, the peroxidation of lipids in membranes or lipoproteins alters lipid function and promotes formation of neo-epitopes, such as oxidation-specific epitopes (OSEs), which are found to be present on (lipo)proteins, dying cells, and extracellular vesicles. Accumulation of OSEs and recognition of OSEs by designated pattern recognition receptors on immune cells or soluble effectors can contribute to the development of chronic inflammatory diseases. In line, recent studies highlight the involvement of modified lipids and OSEs in different stages of the spectrum of non-alcoholic fatty liver disease (NAFLD), including inflammatory non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma. Targeting lipid peroxidation products shows high potential in the search for novel, better therapeutic strategies for NASH.

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A genome-wide association study identifies key modulators of complement factor H binding to malondialdehyde-epitopes

Cited by 31 publications

References 54 publications

Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization

Interaction of the Factor H Family Proteins FHR-1 and FHR-5 With DNA and Dead Cells: Implications for the Regulation of Complement Activation and Opsonization

Complement Factor H-Related 3 induces inflammation and complosome activation in human RPE cells

Oxidation-Specific Epitopes in Non-Alcoholic Fatty Liver Disease

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