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


RESULTS
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.


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.
Hägele
Holger
H
Department of Nephrology, Medical Policlinic, University of Munich, Munich, Germany.
Allam
Ramanjaneyulu
R
Pawar
Rahul D
RD
Anders
Hans-Joachim
HJ
D000418:Albumins / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000502:physiology*; D004705:Endocytosis; D042783:Endothelial Cells / Q000276:immunology*; D005921:Glomerulonephritis / Q000209:etiology*; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007370:Interferon Type I / Q000096:biosynthesis*; D000072640:Interferon-Induced Helicase, IFIH1; D007678:Kidney Glomerulus / Q000276:immunology*; D051379:Mice; D011070:Poly I-C / Q000494:pharmacology; D012327:RNA Virus Infections / Q000150:complications*; D012330:RNA, Double-Stranded / Q000502:physiology*; D051193:Toll-Like Receptors / Q000502:physiology; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000418:Albumins; D007370:Interferon Type I; D012330:RNA, Double-Stranded; D051193:Toll-Like Receptors; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; C503356:Ddx58 protein, mouse; C510592:Ifih1 protein, mouse; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D000072640:Interferon-Induced Helicase, IFIH1; D011070:Poly I-C