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Serum FHR1 Binding to Necrotic-Type Cells Activates Monocytic Inflammasome and Marks Necrotic Sites in Vasculopathies

Serum FHR1 Binding to Necrotic-Type Cells Activates Monocytic Inflammasome and Marks Necrotic Sites in Vasculopathies

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 Wiech, Peter F Zipfel, etc.

Nat Commun. 2019 Jul 4;10(1):2961.

PMID: 31273197

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP80295483	Complement C4 from human serum		80295-48-3	Price

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