Viral RNA and DNA trigger common antiviral responses in mesangial cells.
Extrarenal viral infections commonly trigger glomerulonephritis, usually in association with immune complex disease. The Ig component of immune complexes can activate glomerular cell Fc receptors, but whether complexed viral nucleic acids contribute to glomerular inflammation remains unknown. Because of the types of Toll-like receptors (Tlrs) expressed by glomerular mesangial cells, we hypothesized that viral single-stranded RNA and DNA would activate mesangial cells via Tlr-independent pathways and trigger overlapping antiviral immune responses. Consistent with this hypothesis, 5'-triphosphate RNA (3P-RNA) and non-CpG DNA activated murine primary glomerular mesangial cells to secrete Cxcl10 and Il-6 even in cells derived from mice deficient in the Tlr adaptor proteins Myd88 and Trif. Transcriptome analysis revealed that 3P-RNA and non-CpG-DNA triggered almost identical gene expression programs, especially the proinflammatory cytokine Il-6, several chemokines, and genes related to type I IFN. We observed similar findings in glomerular preparations after injecting 3P-RNA and non-CpG-DNA in vivo. These effects depended on the formation of complexes with cationic lipids, which enhanced nucleic acid uptake into the cytosol of mesangial cells. Small interfering RNA studies revealed that 3P-RNA recognition involves Rig-1, whereas non-CpG-DNA did not require Rig-1 or Dai to activate glomerular mesangial cells. We conclude that 3P-RNA and double-stranded DNA trigger a common, TLR-independent, antiviral response in glomerular mesangial cells, which may promote glomerulonephritis in the setting of viral infection.
Allam
Ramanjaneyulu
R
Medizinische Poliklinik, University of Munich, Munich, Germany.
Lichtnekert
Julia
J
Moll
Anton G
AG
Taubitz
Anela
A
Vielhauer
Volker
V
Anders
Hans-Joachim
HJ
D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002460:Cell Line; D054357:Chemokine CXCL10 / Q000378:metabolism; D018899:CpG Islands / Q000276:immunology; D004279:DNA, Viral / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D005921:Glomerulonephritis / Q000276:immunology* / Q000821:virology*; D006023:Glycoproteins / Q000378:metabolism; D007105:Immune Complex Diseases / Q000276:immunology / Q000821:virology; D007372:Interferons / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050527:Mesangial Cells / Q000166:cytology / Q000276:immunology* / Q000821:virology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D012367:RNA, Viral / Q000276:immunology*; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; D000097905:Roundabout Proteins
D054357:Chemokine CXCL10; D004279:DNA, Viral; D006023:Glycoproteins; D007372:Interferons; D015850:Interleukin-6; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D012367:RNA, Viral; D016601:RNA-Binding Proteins; D011956:Receptors, Cell Surface; C485433:Cxcl10 protein, mouse; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins; C402632:Zbp1 protein, mouse