Inhibition of type I interferon signalling prevents TLR ligand‐mediated proteinuria. Issue 2 (10th September 2013)

• Record Type: Journal Article
• Authors: Gurkan, Sevgi; Cabinian, Allison; Lopez, Victoria; Bhaumik, Mantu; Chang, Jer‐Ming; Rabson, Arnold B; Mundel, Peter
• Is Part Of: Journal of pathology. Volume 231:Issue 2(2013)
• Page Start: 248
• Page End: 256
• Publication Date: 2013-09-10
• Subjects: Pathology -- Periodicals; 616.07
• DOI: 10.1002/path.4235
• Languages: English
• ISSNs: 0022-3417

Abstract

<abstract abstract-type="main" id="path4235-abs-0001"> <title>Abstract</title> <p id="path4235-para-0001"> <bold>The mechanisms by which inflammation or autoimmunity causes proteinuric kidney disease remain elusive. Yet proteinuria is a hallmark and a prognostic indicator of kidney disease, and also an independent risk factor for cardiovascular morbidity and mortality. Podocytes are an integral component of the kidney filtration barrier and podocyte injury leads to proteinuria. Here we show that podocytes, which receive signals from the vascular space including circulating antigens, constitutively express TLR1–6 and TLR8. We find that podocytes can respond to TLR ligands including staphylococcal enterotoxin B (SEB), poly I:C, or lipopolysaccharide (LPS) with pro‐inflammatory cytokine release and activation of type I interferon (IFN) signalling. This in turn stimulates podocyte B7‐1 expression and actin remodelling <italic>in vitro</italic> and transient proteinuria <italic>in vivo</italic>. Importantly, the treatment of mice with a type I IFN receptor‐blocking antibody (Ab) prevents LPS‐induced proteinuria. These results significantly extend our understanding of podocyte response to immune stimuli and reveal a novel mechanism for infection‐ or inflammation‐induced transient proteinuria. Dysregulation or aberrant activation of this response may result in persistent proteinuria and progressive glomerular disease. In summary, the inhibition of glomerular type I IFN signalling with anti‐IFN Abs may be a novel therapy for proteinuric kidney diseases. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.</bold> </p> </abstract>