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

Julia Lichtnekert, Volker Vielhauer, Daniel Zecher, Onkar P. Kulkarni, Sebastian Clauss, Stephan Segerer, Veit Hornung, Tanya N. Mayadas, Bruce Beutler, Shizuo Akira, Hans Joachim Anders

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)F867-F874
JournalAmerican Journal of Physiology - Renal Physiology
Volume296
Issue number4
DOIs
StatePublished - Apr 2009

Keywords

  • Apoptosis
  • Glomerulonephritis
  • Innate immunity
  • Kidney
  • Necrosis
  • Toll-like receptor

ASJC Scopus subject areas

  • Physiology
  • Urology

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