Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

Irmscher, Sarah; Brix, Silke R.; Zipfel, S.; Halder, Luke D.; Mutlutürk, Sibel; Wulf, Sonia; Girdauskas, Evaldas; Reichenspurner, Hermann; Stahl, Rolf A.K.; Jungnickel, Berit; Wiech, Thorsten; Zipfel, Peter F.; Skerka, Christine

doi:10.1038/s41467-019-10766-0

Cited by 46 publications

(76 citation statements)

References 64 publications

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“…6C, lanes 7 and 9, respectively) were used. All mass and molar ratios of CFH to FHR1 used are in agreement with the majority of physiological ratios reported (36,(38)(39)(40)(41)(42). Independent of the concentrations used, cofactor activity for FI was not observed for FHR1 alone (Fig.…”

Section: A Gwas Reveals a Cluster Of Genetic Variants Within Cfhr Gensupporting

confidence: 84%

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

Alic

Papac-Miličević

Rudnick

et al. 2020

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

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Genetic variants within complement factor H (CFH), a major alternative complement pathway regulator, are associated with the development of age-related macular degeneration (AMD) and other complementopathies. This is explained with the reduced binding of CFH or its splice variant factor H-like protein 1 (FHL-1) to self-ligands or altered self-ligands (e.g., malondialdehyde [MDA]-modified molecules) involved in homeostasis, thereby causing impaired complement regulation. Considering the critical role of CFH in inhibiting alternative pathway activation on MDA-modified surfaces, we performed an unbiased genome-wide search for genetic variants that modify the ability of plasma CFH to bind MDA in 1,830 individuals and characterized the mechanistic basis and the functional consequences of this. In a cohort of healthy individuals, we identified rs1061170 in CFH and the deletion of CFHR3 and CFHR1 as dominant genetic variants that modify CFH/FHL-1 binding to MDA. We further demonstrated that FHR1 and FHR3 compete with CFH for binding to MDA-epitopes and that FHR1 displays the highest affinity toward MDA-epitopes compared to CFH and FHR3. Moreover, FHR1 bound to MDA-rich areas on necrotic cells and prevented CFH from mediating its cofactor activity on MDA-modified surfaces, resulting in enhanced complement activation. These findings provide a mechanistic explanation as to why the deletion of CFHR3 and CFHR1 is protective in AMD and highlight the importance of genetic variants within the CFH/CFHR3/CFHR1 locus in the recognition of altered-self in tissue homeostasis.

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Section: A Gwas Reveals a Cluster Of Genetic Variants Within Cfhr Gensupporting

confidence: 84%

“…5G, and SI Appendix, Fig. S9B) (36). These data demonstrate that both FHR1 and FHR3 identify MDA-epitopes at sites of membrane damage, albeit with different affinities.…”

Section: A Gwas Reveals a Cluster Of Genetic Variants Within Cfhr Genmentioning

confidence: 65%

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

Alic

Papac-Miličević

Rudnick

et al. 2020

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

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“…Similar to FHR-5, the extent of FHR-1 binding was increased when the cells became apoptotic or necrotic ( Figure 6 ). A recent study also found FHR-1 binding to necrotic HUVEC but not to live HUVEC ( 59 ). 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 ).…”

Section: Discussionmentioning

confidence: 87%

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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“…Monocytes with CFHR3-CFHR1 deletion secreted higher level of IL-1β in response to LPS challenge (32). Necrotic cells bound to FHR-1 promotes the secretion of TNF-α, IL-1β, IL-18, and IL-6 by monocytes (33). These reports suggest multiple effects of CFHR1 deletion and highlight its complexity.…”

Section: Introductionmentioning

confidence: 85%

Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway

Hao

Liu

et al. 2020

Front. Immunol.

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Alternative complement pathway (AP) plays an important role in the development of sepsis, which is life threatening. Deficiency of factor H-related protein 1 (FHR-1), which is a regulator of AP, has been considered as a susceptible factor for atypical hemolytic uremic syndrome (aHUS) and other types of nephropathy when an inducer such as infection exists. However, the underlying mechanism of the disease development is largely unknown. There is no report on CFHR1 gene knockout in any animal infection model and its function in vivo is still unclear. Here, a Cfhr1 knockout mouse was generated for investigating AP in sepsis and sepsis-induced acute kidney injury (AKI). We found that murine FHR-1 homolog (FHR-E) deficiency enhanced lipopolysaccharide (LPS)-induced AP activation both in vitro and in vivo and that Cfhr1 knockout mice exhibited more severe sepsis and AKI in response to LPS challenge. These results indicated that FHR-E deficiency promoted LPS-induced sepsis and AKI through AP over-activation, providing a mouse model for studying AP regulation and sepsis. This study revealed the function of FHR-E in vivo, which may further provide hints to the pathogenesis of FHR-1 deficiency-related diseases by enhancing LPS-induced AP activation.

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Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies

Cited by 46 publications

References 64 publications

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

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

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

Deficiency of Mouse FHR-1 Homolog, FHR-E, Accelerates Sepsis, and Acute Kidney Injury Through Enhancing the LPS-Induced Alternative Complement Pathway

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