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This Article Full Text Full Text (PDF) All Versions of this Article: 296/4/F867    most recent 90213.2008v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Lichtnekert, J. Articles by Anders, H.-J. Search for Related Content PubMed PubMed Citation Articles by Lichtnekert, J. Articles by Anders, H.-J.

Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif

¹Medical Policlinic, University of Munich, Munich; ²Clinic for Nephrology and Institute of Anatomy, University of Zürich, Switzerland; ³Division of Clinical Pharmacology, Department of Medicine, University of Bonn, Bonn, Germany; ⁴Center of Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts; ⁵Department of Immunology, The Scripps Research Institute, La Jolla, California; and ⁶Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Submitted 1 April 2008 ; accepted in final form 21 January 2009

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.

innate immunity; glomerulonephritis; kidney; necrosis; apoptosis; Toll-like receptor