PMID- 31273197 OWN - NLM STAT- MEDLINE DCOM- 20190910 LR - 20210110 IS - 2041-1723 (Electronic) IS - 2041-1723 (Linking) VI - 10 IP - 1 DP - 2019 Jul 4 TI - Serum FHR1 binding to necrotic-type cells activates monocytic inflammasome and marks necrotic sites in vasculopathies. PG - 2961 LID - 10.1038/s41467-019-10766-0 [doi] LID - 2961 AB - 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-1beta, TNFalpha, 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. FAU - Irmscher, Sarah AU - Irmscher S AD - Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany. FAU - Brix, Silke R AU - Brix SR AD - III. Medical Clinic, University Medical Center Hamburg-Eppendorf, Martini Str. 52, 20246, Hamburg, Germany. FAU - Zipfel, Svante L H AU - Zipfel SLH AD - Clinic for Heart and Visceral Surgery, Center of Heart Diseases, University Hospital Hamburg-Eppendorf, Martini Str. 52, 20251, Hamburg, Germany. FAU - Halder, Luke D AU - Halder LD AD - Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany. FAU - Mutluturk, Sibel AU - Mutluturk S AD - Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany. FAU - Wulf, Sonia AU - Wulf S AD - Institute of Pathology, University Hospital Hamburg-Eppendorf, Martini Str. 52, 20251, Hamburg, Germany. FAU - Girdauskas, Evaldas AU - Girdauskas E AD - Clinic for Heart and Visceral Surgery, Center of Heart Diseases, University Hospital Hamburg-Eppendorf, Martini Str. 52, 20251, Hamburg, Germany. FAU - Reichenspurner, Hermann AU - Reichenspurner H AD - Clinic for Heart and Visceral Surgery, Center of Heart Diseases, University Hospital Hamburg-Eppendorf, Martini Str. 52, 20251, Hamburg, Germany. FAU - Stahl, Rolf A K AU - Stahl RAK AD - III. Medical Clinic, University Medical Center Hamburg-Eppendorf, Martini Str. 52, 20246, Hamburg, Germany. FAU - Jungnickel, Berit AU - Jungnickel B AD - Department of Cell Biology, Institute of Biochemistry and Biophysics, Friedrich-Schiller University, Hans-Knoll Str. 2, 07745, Jena, Germany. FAU - Wiech, Thorsten AU - Wiech T AD - Institute of Pathology, University Hospital Hamburg-Eppendorf, Martini Str. 52, 20251, Hamburg, Germany. FAU - Zipfel, Peter F AU - Zipfel PF AUID- ORCID: 0000-0002-6149-2411 AD - Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany. AD - Faculty of Biological Sciences, Friedrich-Schiller University, Furstengraben 1, 07743, Jena, Germany. FAU - Skerka, Christine AU - Skerka C AUID- ORCID: 0000-0003-2374-6473 AD - Department of Infection Biology, Leibniz Institute for Natural Product Research and Infection Biology, Adolf-Reichwein Str. 23, 07745, Jena, Germany. christine.skerka@hki-jena.de. LA - eng GR - RC 124 Funginet Project C4/Deutsche Forschungsgemeinschaft (German Research Foundation)/International GR - RC 124 Funginet Project C6/Deutsche Forschungsgemeinschaft (German Research Foundation)/International GR - CRC 124 Funginet project C4/Deutsche Forschungsgemeinschaft (German Research Foundation)/International GR - SK 46/2-2/Deutsche Forschungsgemeinschaft (German Research Foundation)/International PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20190704 PL - England TA - Nat Commun JT - Nature communications JID - 101528555 RN - 0 (ADGRE2 protein, human) RN - 0 (CFHR1 protein, human) RN - 0 (Complement C3b Inactivator Proteins) RN - 0 (Immobilized Proteins) RN - 0 (Inflammasomes) RN - 0 (Inflammation Mediators) RN - 0 (Interleukin-1beta) RN - 0 (Lipoproteins, LDL) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Receptors, G-Protein-Coupled) RN - 4Y8F71G49Q (Malondialdehyde) RN - 9007-36-7 (Complement System Proteins) RN - 9007-41-4 (C-Reactive Protein) RN - EC 3.1.4.- (Type C Phospholipases) SB - IM MH - C-Reactive Protein/metabolism MH - Complement C3b Inactivator Proteins/*metabolism MH - Complement System Proteins/metabolism MH - Human Umbilical Vein Endothelial Cells/metabolism MH - Humans MH - Immobilized Proteins/metabolism MH - Inflammasomes/*metabolism MH - Inflammation/metabolism/pathology MH - Inflammation Mediators/metabolism MH - Interleukin-1beta/metabolism MH - Lipoproteins, LDL/metabolism MH - Malondialdehyde/metabolism MH - Models, Biological MH - Monocytes/*metabolism/*pathology MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Necrosis MH - Protein Binding MH - Receptors, G-Protein-Coupled/metabolism MH - Serum/metabolism MH - Type C Phospholipases/metabolism MH - Vascular Diseases/*metabolism/*pathology PMC - PMC6609651 COIS- S.I., P.F.Z., and C.S. have filed a patent (DE10 2018 120 016.1). The remaining authors declare no competing interests. EDAT- 2019/07/06 06:00 MHDA- 2019/09/11 06:00 PMCR- 2019/07/04 CRDT- 2019/07/06 06:00 PHST- 2018/10/25 00:00 [received] PHST- 2019/05/31 00:00 [accepted] PHST- 2019/07/06 06:00 [entrez] PHST- 2019/07/06 06:00 [pubmed] PHST- 2019/09/11 06:00 [medline] PHST- 2019/07/04 00:00 [pmc-release] AID - 10.1038/s41467-019-10766-0 [pii] AID - 10766 [pii] AID - 10.1038/s41467-019-10766-0 [doi] PST - epublish SO - Nat Commun. 2019 Jul 4;10(1):2961. doi: 10.1038/s41467-019-10766-0.