TY - JOUR
T1 - Viral RNA induces type i interferon-dependent cytokine release and cell death in mesangial cells via melanoma-differentiation-associated gene-5
T2 - Implications for viral infection-associated glomerulonephritis
AU - Flür, Katharina
AU - Allam, Ramanjaneyulu
AU - Zecher, Daniel
AU - Kulkarni, Onkar P.
AU - Lichtnekert, Julia
AU - Schwarz, Martin
AU - Beutler, Bruce
AU - Vielhauer, Volker
AU - Anders, Hans Joachim
N1 - Funding Information:
Supported by the Deutsche Forschungsgemeinschaft (AN372/9-1 and GRK 1202; to H.-J.A.). K.F., R.A., and J.L. were graduate fellows of the Deutsche Forschungsgemeinschaft GRK 1202.
PY - 2009
Y1 - 2009
N2 - Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanomadifferentiation-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-β(TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-β 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-α and IFN-β independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-β 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-α and IFN-β, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-αβ 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.
AB - Viral RNA can trigger interferon signaling in dendritic cells via the innate recognition receptors melanomadifferentiation-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-β(TRIF)-deficient mice, which lack a key adaptor for TLR3 signaling. In primary mesangial cells, poly I:C RNA-mediated IFN-β 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-α and IFN-β independent of TRIF. Mesangial cells expressed RIG-I and MDA-5 and their mitochondrial adaptor IFN-β 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-α and IFN-β, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-αβ 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.
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U2 - 10.2353/ajpath.2009.080585
DO - 10.2353/ajpath.2009.080585
M3 - Article
C2 - 19850889
AN - SCOPUS:73649090376
SN - 0002-9440
VL - 175
SP - 2014
EP - 2022
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 5
ER -