Published online before print October 22, 2009

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(American Journal of Pathology. 2009;175:2014-2022.)
© 2009 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2009.080585

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

Katharina Flür^*, Ramanjaneyulu Allam^*, Daniel Zecher^*, Onkar P. Kulkarni^*, Julia Lichtnekert^*, Martin Schwarz^*, Bruce Beutler, Volker Vielhauer^* and Hans-Joachim Anders^*

From the Medical Policlinic,^* University of Munich, Munich, Germany; and the Department of Genetics, The Scripps Research Institute, La Jolla, California

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-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- 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- and IFN-β, suggesting an autocrine proinflammatory effect. Indeed, blockade of IFN-β 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.