Viral RNA induces type I interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5: Implications for viral infection-associated glomerulonephritis.
Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanoma-differentiation-associated gene (MDA)-5 and retinod-inducible gene (RIG)-I in the cytosol or via Toll-like receptors (TLRs) in intracellular endosomes. We hypothesized that viral RNA would also activate glomerular mesangial cells to produce type I interferon (IFN) via TLR-dependent and TLR-independent pathways. To test this hypothesis, we examined Toll/Interleukin-1 receptor domain-containing adaptor-inducing interferon-beta (TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-beta induction was partially TRIF dependent; however, when poly I:C RNA was complexed with cationic lipids to enhance cytosolic uptake, mesangial cells produced large amounts of IFN-alpha and IFN-beta independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-beta promoter stimulator-1 as well, and small interfering RNA studies revealed that MDA5 but not RIG-I was required for cytosolic poly I:C RNA signaling. In addition, mesangial cells produced Il-6 on stimulation with IFN-alpha and IFN-beta, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-alphabeta or lack of the IFNA receptor reduced viral RNA-induced Il-6 production and apoptotic cell death in mesangial cells. Furthermore, viral RNA/cationic lipid complexes increased focal necrosis in murine nephrotoxic serum nephritis in association with increased renal mRNA expression of IFN-related genes. Thus, TLR-independent recognition of viral RNA is a potent inducer of type I interferon in mesangial cells, which can be an important mediator of virally induced glomerulonephritis.
Medical Policlinic, University of Munich, Germany.
Katharina
K
Flür
Ramanjaneyulu
R
Allam
Daniel
D
Zecher
Onkar P
OP
Kulkarni
Julia
J
Lichtnekert
Martin
M
Schwarz
Bruce
B
Beutler
Volker
V
Vielhauer
Hans-Joachim
HJ
Anders
D000818:Animals; D016923:Cell Death / Q000276:immunology*; D016207:Cytokines / Q000276:immunology*; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000473:pathology / Q000821:virology; D007370:Interferon Type I / Q000276:immunology*; D000072640:Interferon-Induced Helicase, IFIH1; D007678:Kidney Glomerulus / Q000166:cytology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D050527:Mesangial Cells / Q000473:pathology / Q000502:physiology / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D009393:Nephritis / Q000097:blood / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011070:Poly I-C / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012367:RNA, Viral / Q000235:genetics / Q000378:metabolism*; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors / Q000378:metabolism; D000097905:Roundabout Proteins
D016207:Cytokines; D053487:DEAD-box RNA Helicases; D007370:Interferon Type I; D000072640:Interferon-Induced Helicase, IFIH1; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D011070:Poly I-C; D034741:RNA, Small Interfering; D012367:RNA, Viral; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C510592:Ifih1 protein, mouse