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

Author

Listed:
  • Sarah Irmscher

    (Leibniz Institute for Natural Product Research and Infection Biology)

  • Silke R. Brix

    (University Medical Center Hamburg-Eppendorf)

  • Svante L. H. Zipfel

    (University Hospital Hamburg-Eppendorf)

  • Luke D. Halder

    (Leibniz Institute for Natural Product Research and Infection Biology)

  • Sibel Mutlutürk

    (Leibniz Institute for Natural Product Research and Infection Biology)

  • Sonia Wulf

    (University Hospital Hamburg-Eppendorf)

  • Evaldas Girdauskas

    (University Hospital Hamburg-Eppendorf)

  • Hermann Reichenspurner

    (University Hospital Hamburg-Eppendorf)

  • Rolf A. K. Stahl

    (University Medical Center Hamburg-Eppendorf)

  • Berit Jungnickel

    (Friedrich-Schiller University)

  • Thorsten Wiech

    (University Hospital Hamburg-Eppendorf)

  • Peter F. Zipfel

    (Leibniz Institute for Natural Product Research and Infection Biology
    Friedrich-Schiller University)

  • Christine Skerka

    (Leibniz Institute for Natural Product Research and Infection Biology)

Abstract

Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. Here, we describe a dominant trigger of inflammation: human serum factor H-related protein FHR1. In vitro, this protein selectively binds to necrotic cells via its N-terminus; in addition, it binds near necrotic glomerular sites of AAV patients and necrotic areas in atherosclerotic plaques. FHR1, but not factor H, FHR2 or FHR3 strongly induces inflammasome NLRP3 in blood-derived human monocytes, which subsequently secrete IL-1β, TNFα, IL-18 and IL-6. FHR1 triggers the phospholipase C-pathway via the G-protein coupled receptor EMR2 independent of complement. Moreover, FHR1 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. These data highlight an unexpected role for FHR1 during sterile inflammation, may explain why FHR1-deficiency protects against certain diseases, and identifies potential targets for treatment of auto-inflammatory diseases.

Suggested Citation

  • Sarah Irmscher & Silke R. Brix & Svante L. H. Zipfel & Luke D. Halder & Sibel Mutlutürk & Sonia Wulf & Evaldas Girdauskas & Hermann Reichenspurner & Rolf A. K. Stahl & Berit Jungnickel & Thorsten Wiec, 2019. "Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-10766-0
    DOI: 10.1038/s41467-019-10766-0
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    Cited by:

    1. Valur Emilsson & Elias F. Gudmundsson & Thorarinn Jonmundsson & Brynjolfur G. Jonsson & Michael Twarog & Valborg Gudmundsdottir & Zhiguang Li & Nancy Finkel & Stephen Poor & Xin Liu & Robert Esterberg, 2022. "A proteogenomic signature of age-related macular degeneration in blood," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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