Double-stranded RNA activates type I interferon secretion in glomerular endothelial cells via retinoic acid-inducible...

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.

Cultured murine GEnC were stimulated with poly I:C 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.

Poly I:C 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.

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.