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.
Highlights
Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis
To investigate whether FHR1 modulates inflammation, we coated microtiter plates with FHR1 and incubated it with freshly isolated human peripheral blood monocytes in normal human serum (NHS) with or without lipopolysaccharide (LPS)
The results showed that FHR1 alone strongly induced release of the pro-inflammatory cytokine IL-1β from monocytes, and increased LPS-triggered secretion of IL-1β (Fig. 1a)
Summary
Persistent inflammation is a hallmark of many human diseases, including anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) and atherosclerosis. 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 concentrations of AAV patients negatively correlate with glomerular filtration rates and associate with the levels of inflammation and progressive disease. Cellular stress is a spontaneous event triggered by injury or infection and is a characteristic of inflammatory diseases, such as anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV)[1] and atherosclerosis (AS)[2, 3]. Patients with AS show high activation of the inflammasome 3 (NLRP3) in the aorta[2, 3]
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