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, Hans Joachim Anders

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2014-2022
Number of pages9
JournalAmerican Journal of Pathology
Volume175
Issue number5
DOIs
StatePublished - Jan 1 2009

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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