Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif
Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif
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DOI：
10.1152/ajprenal.90213.2008
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发表时间：
2009-04-01
影响因子：
4.2
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
--
作者：
Lichtnekert, Julia;Vielhauer, Volker;Anders, Hans-Joachim
[10] Lichtnekert J，Vielhauer V，Zecher D，Kulkarni OP，Clauss S，Segerer S，Hornung V，Mayadas TN，Beutler B，Akira S，Anders H.免疫复合物肾小球肾炎不需要Trif：垂死细胞通过Tlr 2/Myd 88而不是Tlr 3/Trif激活系膜细胞。美国肾脏生理学杂志296：F867-F874，2009年。首次发表于2009年1月21日; doi：10.1152/ajprenal.90213.2008。病毒RNA或细菌产物可以通过Toll样受体（Tlr）的一个子集激活肾小球系膜细胞。由于Tlr 2缺陷小鼠最近被发现有减弱肾毒性血清肾炎（NSN），我们假设内源性Tlr激动剂可以激活肾小球系膜细胞。C57 BL/6小鼠的原代系膜细胞在相当水平上表达Tlr 1 -6和Tlr 11 mRNA，并且当暴露于相应的Tlr配体时产生IL-6。暴露于坏死细胞激活培养的原代系膜细胞产生IL-6在Tlr 2/Myd 88依赖的方式。凋亡细胞只有在大量富集时才能激活培养的系膜细胞。凋亡细胞诱导的IL-6释放是Myd 88依赖性的，只有纯化的凋亡细胞RNA诱导系膜细胞中的Trif信号。Trif信号传导是否有助于肾小球肾炎的疾病活动？为了回答这个问题，我们通过在Trif突变型和野生型小鼠中注射在兔中产生的NS来诱导自体NSN。缺乏Trif并没有改变NSN的功能和组织形态学异常，包括抗兔IgG和抗兔特异性致肾炎T细胞的演变。因此，我们得出结论，凋亡细胞RNA是系膜细胞中Trif信号传导的不良激活剂，坏死细胞的释放通过Tlr 2/Myd 88信号传导途径激活系膜细胞。
Lichtnekert J, Vielhauer V, Zecher D, Kulkarni OP, Clauss S, Segerer S, Hornung V, Mayadas TN, Beutler B, Akira S, Anders H. Trif is not required for immune complex glomerulonephritis: dying cells activate mesangial cells via Tlr2/Myd88 rather than Tlr3/Trif. Am J Physiol Renal Physiol 296: F867-F874, 2009. First published January 21, 2009; doi:10.1152/ajprenal.90213.2008.-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.