Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus
Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus
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DOI：
10.1002/art.22524
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发表时间：
2007-05-01
影响因子：
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通讯作者：
Remuzzi, Giuseppe
中科院分区：
文献类型：
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作者：
Benigni, Ariela;Caroli, Cristina;Remuzzi, Giuseppe
客观的。 Toll 样受体 9 (TLR-9) 是一种 CpG DNA 受体，与狼疮免疫细胞的激活有关。我们进行这项研究是为了确定狼疮性肾炎常驻肾细胞中TLR-9的表达是否与肾小管间质损伤的发生有关。方法。通过激光捕获显微切割结合实时定量逆转录酶-聚合酶链反应，对不同疾病阶段的 (NZB X NZW)F-1 小鼠选择性回收的肾组织中的 TLR-9 进行分析，并通过免疫组织化学对狼疮性肾炎患者的肾活检标本中的 TLR-9 进行分析。我们通过培养狼疮患者血清中的近端肾小管细胞，研究了负责 TLR-9 激活的分子成分。结果。 NZB X NZW 小鼠的肾组织显示出位于近端肾小管细胞的强劲 TLR-9 表达。 TLR-9 水平与蛋白尿和肾小管间质损伤相关，以至于细胞周期蛋白依赖性激酶抑制剂在减少蛋白尿和肾结构损伤的同时，还能阻止狼疮小鼠肾小管 TLR-9 的生成。一致地，在狼疮患者的近端肾小管细胞中发现了过度的 TLR-9 染色，这与肾小管间质损伤相关。从狼疮患者血清中纯化的含 DNA 免疫复合物在培养的近端肾小管细胞中诱导 TLR-9。富含 CCGG 的短寡核苷酸（CpG DNA 的特异性拮抗剂）可以阻止这种情况，表明免疫复合物的 DNA 成分是 TLR-9 刺激所必需的。结论。这些发现表明，肾小管 TLR-9 激活在实验性狼疮性肾炎和人类狼疮性肾炎的肾小管间质炎症和损伤中具有致病作用，并且它们为未来治疗指明了新的靶点。
Objective. Toll-like receptor 9 (TLR-9), a receptor for CpG DNA, has been implicated in the activation of immune cells in lupus. We undertook this study to determine whether the expression of TLR-9 in resident renal cells in lupus nephritis is related to the development of tubulointerstitial injury.Methods. TLR-9 was analyzed in selectively retrieved renal tissue from (NZB X NZW)F-1 mice at different stages of disease by laser capture microdissection combined with real-time quantitative reverse transcriptase-polymerase chain reaction, and in renal biopsy specimens from lupus nephritis patients by immunohistochemistry. We investigated for the molecular component responsible for TLR-9 activation by cultured proximal tubular cells in serum from patients with lupus.Results. Renal tissue from NZB X NZW mice displayed robust TLR-9 expression localized to proximal tubular cells. TLR-9 levels correlated with proteinuria and tubulointerstitial injury to the extent that a cyclin-dependent kinase inhibitor, while reducing proteinuria and renal structural damage, prevented tubular TLR-9 generation in lupus mice. Consistently, exaggerated TLR-9 staining was found in proximal tubular cells of lupus patients, which correlated with tubulointerstitial damage. DNA-containing immune complexes purified from sera of patients with lupus induced TLR-9 in cultured proximal tubular cells. This was prevented by CCGG-rich short oligonucleotides, specific antagonists of CpG DNA, indicating that the DNA component of immune complexes was required for TLR-9 stimulation.Conclusion. These findings suggest that tubular TLR-9 activation has a pathogenetic role in tubulointerstitial inflammation and damage in experimental and human lupus nephritis, and they indicate a novel target for future therapies.