Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible gene (RIG)-1.

ABSTRACT

BACKGROUND: The molecular pathomechanisms by which viral infections trigger glomerulonephritis remain elusive. In the glomerulus, glomerular endothelial cells (GEnC) first interact with circulating viral particles; hence, we hypothesized that viral RNA, a known inducer of type I interferons and cytokines in dendritic cells, would also elicit proinflammatory antiviral reponses in GEnC. METHODS: Cultured murine GEnC were stimulated with poly IC RNA and phenotype changes were assessed. Specific antagonists or s.i.RNA were used to determine the mechanisms of RNA uptake and the functional role of putative RNA receptors. RESULTS: Poly IC RNA activated GEnC to produce IL-6, CCL2, CCL5, CXCL10, IFN-alpha and IFN-beta. This was independent of endosomal acidification or MyD88 but required complex formation with cationic lipids to be taken up into GEnC via clathrin-dependent endocytosis. RIG-1- but not MDA5-specific s.i.RNA prevented GEnC activation. Type I interferon production did not activate GEnC in an autocrine-paracrine manner. Complexed RNA also activated GEnC to express ICAM-1 and increased the albumin permeability of GEnC monolayers. CONCLUSIONS: Complexed dsRNA enters GEnC via clathrin endocytosis and activates GEnC via RIG-1 in the cytosol to produce inflammatory cytokines, chemokines and type I interferons. Furthermore, RNA induces ICAM-1 expression and increases GEnC permeability. All of these mechanisms may contribute to the onset or aggravation of glomerulonephritis associated with RNA virus infections.