Inhibition of type I interferon signalling prevents TLR ligand-mediated proteinuria

Abstract

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 in vitro and transient proteinuria in vivo. 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.

Selective IRAK4 Inhibition Attenuates Disease in Murine Lupus Models and Demonstrates Steroid Sparing Activity

“…At the level of histology, glomerular damage was more significantly suppressed relative to tubulointerstitial and tubular end points. In addition to expression on infiltrating lymphoid and myeloid cells, TLRs are expressed by several kidney-resident cell populations, including podocytes (33). These cells may respond to any damage-associated molecular pattern molecules released in response to tissue damage (34).…”

“…BMS-986126 was also tested against a panel of 338 kinase assays using 33 P incorporation at Reaction Biology (Malvern, PA). Each kinase was tested individually in duplicate with 1 mM BMS-986126 and 10 mM ATP.…”

Beyond Tissue Injury—Damage-Associated Molecular Patterns, Toll-Like Receptors, and Inflammasomes Also Drive Regeneration and Fibrosis

“…Additional cell type-specific effects include the upregulation of adhesion molecules, increased vascular permeability in renal endothelial cells, and filtration barrier dysfunction in podocytes. [89][90][91][92][93] Resident and infiltrating mononuclear phagocytes also host the NLRP3 inflammasome that integrates DAMP signals such as ATP, histones, HA, biglycan, crystals, or uromodulin into the activation of caspase-1. 81,[94][95][96][97] Caspase-1 and caspase-11 confer proteolytic cleavage of pro-IL1b and pro-IL-18 into the mature cytokines, which are then secreted and trigger local inflammation inside the kidney (reviewed in ref.…”

Developing therapeutic ‘arrows’ with the precision of William Tell

“…Gurkan and colleagues recently showed that podocytes, which receive signals from the vascular space, including circulating antigens, constitutively express TLR1–6 and TLR8 [18]. They additionally found that podocytes can respond to TLR ligands including staphylococcal enterotoxin, poly I:C, or lipopolysaccharide with pro-inflammatory cytokine release and activation of type I interferon signaling [18]. This induced podocyte CD80 expression, and transient proteinuria, which could be blocked by a type I interferon receptor-blocking antibody [18].…”

“…They additionally found that podocytes can respond to TLR ligands including staphylococcal enterotoxin, poly I:C, or lipopolysaccharide with pro-inflammatory cytokine release and activation of type I interferon signaling [18]. This induced podocyte CD80 expression, and transient proteinuria, which could be blocked by a type I interferon receptor-blocking antibody [18]. This study significantly extended our understanding of podocyte responses to immune stimuli and revealed a novel mechanism for infection- or inflammation-induced proteinuria in a CD80-dependent, T-cell independent manner.…”