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Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88
Julia Lichtnekert1, Volker Vielhauer, Daniel Zecher
1Medizinische Poliklinik, Klinikum der Universität-Innenstadt, Pettenkoferstr. 8a, 80336 Munich, Germany.
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.
Insights
Necrotic cells activate kidney mesangial cells via Toll-like receptor 2 (Tlr2) and Myd88 signaling. Apoptotic cell RNA poorly activates Trif signaling, indicating Tlr2/Myd88 is key in nephrotoxic serum nephritis.
Area of Science:
- Immunology
- Nephrology
- Cell Biology
Background:
- Glomerular mesangial cells can be activated by viral RNA or bacterial products through Toll-like receptors (Tlr).
- Toll-like receptor 2 (Tlr2)-deficient mice exhibit reduced nephrotoxic serum nephritis (NSN) severity.
- This suggests endogenous Tlr agonists may activate glomerular mesangial cells.
Purpose of the Study:
- To investigate the role of Tlr signaling in activating glomerular mesangial cells.
- To determine the specific Tlr pathways involved in response to necrotic and apoptotic cells.
- To assess the contribution of Trif signaling in the pathogenesis of glomerulonephritis.
Main Methods:
- Primary mouse mesangial cells were cultured and analyzed for Tlr mRNA expression.
- Cells were stimulated with Tlr ligands, necrotic cells, or apoptotic cells to measure Il-6 production.
- Nephrotoxic serum nephritis was induced in wild-type and Trif-mutant mice to evaluate disease progression.
Main Results:
- Mesangial cells express Tlr1-6 and Tlr11 mRNA and produce Il-6 in response to Tlr ligands.
- Necrotic cells activated mesangial cells via a Tlr2/Myd88-dependent pathway.
- Apoptotic cells induced Il-6 release in a Myd88-dependent manner, with RNA activating Trif signaling, but Trif deficiency did not impact NSN severity.
Conclusions:
- Necrotic cell components activate mesangial cells primarily through the Tlr2/Myd88 pathway.
- Apoptotic cell RNA is a weak activator of Trif signaling in mesangial cells.
- Trif signaling does not significantly contribute to the disease activity in nephrotoxic serum nephritis.
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