Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction.
Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction.
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DOI：
10.1371/journal.pone.0019204
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发表时间：
2011-04-22
期刊：
影响因子：
3.7
通讯作者：
Anders HJ
中科院分区：
文献类型：
--
作者：
Skuginna V;Lech M;Allam R;Ryu M;Clauss S;Susanti HE;Römmele C;Garlanda C;Mantovani A;Anders HJ
通过IL-1R或toll样受体（TLR）激活的先天免疫有助于急性肾损伤，但其在慢性肾脏疾病中组织重塑中的作用尚不清楚。SIGIRR是肾内免疫细胞中tlr诱导的细胞因子和趋化因子表达的抑制剂，因此，我们假设SIGIRR缺乏会加重梗阻性肾纤维化。与未阻塞肾脏相比，阻塞肾脏中TLR及内源性TLR激动剂的表达在UUO后6天内升高，而SIGIRR本身在第10天下调。然而，缺乏SIGIRR并不影响肾内促炎和促纤维化介质的mRNA表达，也不影响肾内巨噬细胞和T细胞的数量，或肾小管萎缩和间质纤维化的形态计量学标志物。由于已知SIGIRR在细胞内接头分子MyD88水平上阻断TLR/IL-1R信号传导，UUO实验也在MyD88、TLR2或TLR9缺失的小鼠中进行。与野生型小鼠相比，UUO后两种小鼠的小管间质损伤和间质纤维化均无显著变化。另外对CD90+肾成纤维细胞的体外研究表明，TLR激动剂诱导IL-6和MCP-1/CCL2的表达，但不诱导TGF-β、胶原-1α或平滑肌肌动蛋白的表达。总之，梗阻性肾间质纤维化和肾小管萎缩的发生与SIGIRR、TLR2、TLR9和MyD88无关。这些数据反驳了这些分子在肾纤维化中的重要作用。
Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis.
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影响因子：
32.4
作者：
Kawai, T;Adachi, O;Akira, S
通讯作者：
Akira, S
DOI：
10.1152/ajprenal.90213.2008
发表时间：
2009-04-01
影响因子：
4.2
作者：
Lichtnekert, Julia;Vielhauer, Volker;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
影响因子：
6
作者：
Ninichuk, Volha;Khandoga, Alexander G.;Anders, Hans-Joachim
通讯作者：
Anders, Hans-Joachim
影响因子：
4.4
作者：
Cunningham, PN;Wang, Y;Quigg, RJ
通讯作者：
Quigg, RJ
影响因子：
15.9
作者：
Leemans, JC;Stokman, G;Florquin, S
通讯作者：
Florquin, S