Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif.
Viral RNA or bacterial products can activate glomerular mesangial cells via a subset of Toll-like receptors (Tlr). Because Tlr2-deficient mice were recently found to have attenuated nephrotoxic serum nephritis (NSN), we hypothesized that endogenous Tlr agonists can activate glomerular mesangial cells. Primary mesangial cells from C57BL/6 mice expressed Tlr1-6 and Tlr11 mRNA at considerable levels and produced Il-6 when being exposed to the respective Tlr ligands. Exposure to necrotic cells activated cultured primary mesangial cells to produce Il-6 in a Tlr2/Myd88-dependent manner. Apoptotic cells activated cultured mesangial cells only when being enriched to high numbers. Apoptotic cell-induced Il-6 release was Myd88 dependent, and only purified apoptotic cell RNA induced Trif signaling in mesangial cells. Does Trif signaling contribute to disease activity in glomerulonephritis? To answer this question, we induced autologous NSN by injection of NS raised in rabbits in Trif-mutant and wild-type mice. Lack of Trif did not alter the functional and histomorphological abnormalities of NSN, including the evolution of anti-rabbit IgG and anti-rabbit-specific nephritogenic T cells. We therefore conclude that apoptotic cell RNA is a poor activator of Trif signaling in mesangial cells and that necrotic cells' releases rather activate mesangial cells via the Tlr2/Myd88 signaling pathway.
Lichtnekert
Julia
J
Medizinische Poliklinik, Klinikum der Universität-Innenstadt, Pettenkoferstr. 8a, 80336 Munich, Germany.
Vielhauer
Volker
V
Zecher
Daniel
D
Kulkarni
Onkar P
OP
Clauss
Sebastian
S
Segerer
Stephan
S
Hornung
Veit
V
Mayadas
Tanya N
TN
Beutler
Bruce
B
Akira
Shizuo
S
Anders
Hans-Joachim
HJ
D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000917:Antibody Formation; D000936:Antigen-Antibody Complex / Q000378:metabolism; D017209:Apoptosis; D002478:Cells, Cultured; D054370:Chemokine CXCL9 / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007105:Immune Complex Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D050527:Mesangial Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis; D009404:Nephrotic Syndrome / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000378:metabolism; D011817:Rabbits; D015398:Signal Transduction; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*
D033942:Adaptor Proteins, Vesicular Transport; D000936:Antigen-Antibody Complex; D054370:Chemokine CXCL9; D007371:Interferon-gamma; D015850:Interleukin-6; D053594:Myeloid Differentiation Factor 88; D012313:RNA; D051195:Toll-Like Receptor 2; D051196:Toll-Like Receptor 3; C485969:Cxcl9 protein, mouse; C507780:Myd88 protein, mouse; C476286:Ticam1 protein, mouse; C519703:TLR3 protein, mouse; C493486:Tlr2 protein, mouse