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.

Abstract

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.

• Authors: Katharina Flür, Ramanjaneyulu Allam, Daniel Zecher, Onkar P Kulkarni, Julia Lichtnekert, Martin Schwarz, Bruce Beutler, Volker Vielhauer, Hans-Joachim Anders
• Journal: The American journal of pathology (Am J Pathol) Vol. 175 Issue 5 Pg. 2014-22 (Nov 2009) ISSN: 1525-2191 [Electronic] United States
• PMID: 19850889 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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