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

Am J Pathol. 2009 Nov;175(5):2014-22. doi: 10.2353/ajpath.2009.080585. Epub 2009 Oct 22.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / immunology*
  • Cytokines / immunology*
  • DEAD-box RNA Helicases / genetics
  • DEAD-box RNA Helicases / metabolism*
  • Female
  • Glomerulonephritis* / immunology
  • Glomerulonephritis* / pathology
  • Glomerulonephritis* / virology
  • Interferon Type I / immunology*
  • Interferon-Induced Helicase, IFIH1
  • Kidney Glomerulus / cytology
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mesangial Cells* / pathology
  • Mesangial Cells* / physiology
  • Mesangial Cells* / virology
  • Mice
  • Mice, Inbred C57BL
  • Nephritis / blood
  • Nephritis / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Poly I-C / genetics
  • Poly I-C / metabolism
  • RNA, Small Interfering / genetics
  • RNA, Small Interfering / metabolism
  • RNA, Viral / genetics
  • RNA, Viral / metabolism*
  • Receptors, Cell Surface
  • Toll-Like Receptors / metabolism


  • Cytokines
  • Interferon Type I
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RNA, Small Interfering
  • RNA, Viral
  • Receptors, Cell Surface
  • Robo3 protein, mouse
  • Toll-Like Receptors
  • Ifih1 protein, mouse
  • DEAD-box RNA Helicases
  • Interferon-Induced Helicase, IFIH1
  • Poly I-C