Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice
Expression and regulation of Toll-like receptors in lupus-like immune complex glomerulonephritis of MRL-Fas(lpr) mice
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DOI：
10.1093/ndt/gfl336
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发表时间：
2006-11-01
影响因子：
6.1
通讯作者：
Anders, Hans-Joachim
中科院分区：
文献类型：
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作者：
Patole, Prashant S.;Pawar, Rahul D.;Anders, Hans-Joachim
背景资料。微生物感染如何加剧免疫复合体肾小球肾炎仍在猜测中。Toll样受体可能参与了这种现象，因为当Toll样受体与特定的病原体相关分子接触时，Toll样受体具有强大的免疫刺激功能。我们通过表征TLR1-9在MRLlpr/LPR小鼠中的表达来解决这个问题，MRLlpr/LPR小鼠自发发展为免疫复合体肾炎，作为系统性狼疮样自身免疫综合征的一部分。5周龄健康的MRLlpr/lpr小鼠在肾脏中的表达水平与在脾中的水平相当，而所有其他TLR在肾脏中的表达水平较低。在出生20周的肾炎性MRLlpr/LPR小鼠中，TLR1-9的肾脏mRNA水平增加。激光捕获显微切割肾小球的实时RT-PCR证实，肾脏TLR mRNA至少部分起源于肾小球。TLR3、TLR7和TLR9免疫组织化学染色显示，20周龄肾炎MRLlpr/LPR小鼠F4/80阳性浸润性巨噬细胞表达TLR3、TLR7和TLR9。此外，TLR3定位于肾小球系膜细胞。培养的系膜细胞表达TLR1-4和TLR6，而小鼠巨噬细胞表达TLR1-9。肿瘤坏死因子-α和干扰素-γ诱导系膜细胞TLR2、TLR3和TLR6mRNA表达，下调巨噬细胞TLR1-9mRNA表达。用TLR1-4、TLR5、TLR7和TLR9的配体刺激这两种细胞产生的IL-6与它们各自的TLR表达模式一致。肿瘤坏死因子-α和干扰素-γ促进配体诱导两种细胞产生IL-6，而不考虑它们对各自TLR基因水平的调节作用。因此，TLRs的细胞类型特异性表达和调控可能参与了MRLlpr/lpr小鼠免疫复合体肾炎的感染相关性加重。
Background. How microbial infections exacerbate immune complex glomerulonephritis remains speculative. Toll-like receptors (TLRs) may be involved in this phenomenon, because TLRs have potent immunostimulatory functions when exposed to selected pathogen-associated molecules.Methods. We addressed this issue by characterizing the expression of TLR1-9 in MRLlpr/lpr mice that spontaneously develop immune complex glomerulonephritis as part of a systemic lupus-like autoimmune syndrome.Results. Five-week-old healthy MRLlpr/lpr mice expressed TLR3 mRNA in kidneys at comparable levels as in the spleen, while all other TLRs were expressed at low levels in the kidney. In 20-week-old nephritic MRLlpr/lpr mice, renal mRNA levels had increased for TLR1-9. Renal TLR mRNA originated at least in part from glomeruli as evidenced by real-time RT-PCR from laser capture microdissected glomeruli. Immunostaining for TLR3, TLR7 and TLR9 revealed their expression by F4/80-positive infiltrating macrophages in 20-week-old nephritic MRLlpr/lpr mice. In addition, TLR3 localized to glomerular mesangial cells. Cultured mesangial cells expressed TLR1-4 and TLR6, while murine macrophages expressed TLR1-9. TNF-alpha and IFN-gamma induced TLR2, TLR3 and TLR6 mRNA in mesangial cells, while they down-regulated TLR1-9 mRNA in macrophages. Stimulation of both cell types with ligands for TLR1-4, TLR5, TLR7 and TLR9 induced IL-6 production consistent with their respective TLR expression patterns. TNF-alpha and IFN-gamma enhanced ligand-induced IL-6 production in both cell types irrespective of their modulatory effect on respective TLR mRNA levels.Conclusion. Thus, cell-type-specific expression and regulation of TLRs may be involved in infection-associated exacerbation of immune complex glomerulonephritis of MRLlpr/lpr mice.