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

48 Citations (Scopus)

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 - 2009

Fingerprint

Mesangial Cells
Viral RNA
Virus Diseases
Glomerulonephritis
Interferons
Melanoma
Cell Death
Cytokines
Genes
Toll-Like Receptors
Poly I-C
Interferon Type I
Lipids
Interleukin-1 Receptors
Nephritis
Endosomes
Cytosol
Dendritic Cells
Small Interfering RNA
Necrosis

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

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. / Flür, Katharina; Allam, Ramanjaneyulu; Zecher, Daniel; Kulkarni, Onkar P.; Lichtnekert, Julia; Schwarz, Martin; Beutler, Bruce; Vielhauer, Volker; Anders, Hans Joachim.

In: American Journal of Pathology, Vol. 175, No. 5, 2009, p. 2014-2022.

Research output: Contribution to journalArticle

Flür, Katharina ; Allam, Ramanjaneyulu ; Zecher, Daniel ; Kulkarni, Onkar P. ; Lichtnekert, Julia ; Schwarz, Martin ; Beutler, Bruce ; Vielhauer, Volker ; Anders, Hans Joachim. / 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. In: American Journal of Pathology. 2009 ; Vol. 175, No. 5. pp. 2014-2022.
@article{dc0766de5e63465590f6cf70091d14e3,
title = "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 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.",
author = "Katharina Fl{\"u}r and Ramanjaneyulu Allam and Daniel Zecher and Kulkarni, {Onkar P.} and Julia Lichtnekert and Martin Schwarz and Bruce Beutler and Volker Vielhauer and Anders, {Hans Joachim}",
year = "2009",
doi = "10.2353/ajpath.2009.080585",
language = "English (US)",
volume = "175",
pages = "2014--2022",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "5",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=73649090376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=73649090376&partnerID=8YFLogxK

U2 - 10.2353/ajpath.2009.080585

DO - 10.2353/ajpath.2009.080585

M3 - Article

VL - 175

SP - 2014

EP - 2022

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 5

ER -