Medical Research Council Centre for Transplantation, King's College London School of Medicine, London, UK.
Am J Pathol. 2010 Aug;177(2):644-53. doi: 10.2353/ajpath.2010.091279. Epub 2010 Jun 21.
A role for toll-like receptor 4 (TLR4) has been suggested in previous studies of glomerulonephritis, but the complex integration of these effects has not been explored. To separate effects on the innate and adaptive immune responses, we use the autologous nephrotoxic nephritis model with two disease induction protocols. First, we give a TLR4 ligand at the time of immunization and show the effects are mediated via TLR4 by comparing wild-type and TLR4-deficient mice. In wild-type mice histological measures of disease and serum creatinine are all at least twice as high as TLR4-deficient mice, due to an enhanced immune response to the nephritogenic sheep IgG. Second, we stimulate TLR4 later in the course of disease development and construct four groups of bone marrow chimeric or sham chimeric mice to study the role of TLR4 on bone marrow or renal cells. The most striking finding is that renal cell TLR4 stimulation increases glomerular crescent formation, with a mean of 21% and 25% in the two groups of mice with renal cell TLR4 compared with 0.1% and 0.6% in the two groups without, with differences mirrored by changes in serum creatinine. These findings, in a single disease model, illustrate that TLR4 stimulation triggers crescentic glomerulonephritis by effects on both the adaptive and innate immune response, with a crucial direct effect on renal cells.
先前的肾小球肾炎研究表明 Toll 样受体 4（TLR4）发挥了一定作用，但这些作用的复杂整合尚未得到探索。为了分离先天免疫和适应性免疫反应的影响，我们使用具有两种疾病诱导方案的自体肾毒性肾炎模型。首先，我们在免疫时给予 TLR4 配体，并通过比较野生型和 TLR4 缺陷型小鼠来证明这些作用是通过 TLR4 介导的。在野生型小鼠中，由于对致肾炎羊 IgG 的免疫反应增强，组织学疾病指标和血清肌酐均至少是 TLR4 缺陷型小鼠的两倍。其次，我们在疾病发展过程中晚期刺激 TLR4，并构建四组骨髓嵌合或假嵌合小鼠，以研究 TLR4 在骨髓或肾细胞上的作用。最引人注目的发现是，肾细胞 TLR4 刺激增加了肾小球新月体形成，与两组肾细胞 TLR4 相比，两组没有 TLR4 的小鼠分别为 21%和 25%，血清肌酐的变化反映了相同的变化。这些在单一疾病模型中的发现表明，TLR4 刺激通过对适应性和先天免疫反应的影响引发新月体肾小球肾炎，对肾细胞具有直接关键作用。
