TLR4 links podocytes with the innate immune system to mediate glomerular injury
TLR4 links podocytes with the innate immune system to mediate glomerular injury
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DOI：
10.1681/asn.2007040395
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发表时间：
2008-04-01
影响因子：
13.6
通讯作者：
Alpers, Charles E.
中科院分区：
文献类型：
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作者：
Banas, Miriam C.;Banas, Bernhard;Alpers, Charles E.
Toll样受体（TLR）通常识别病原体相关的危险信号，但也通过内源性配体激活。为了评价TLR在炎症性肾病中的作用，在两种冷球蛋白血症膜增生性肾小球肾炎小鼠模型（MPGN;胸腺基质淋巴细胞生成素[TSLP]转基因小鼠，缺失或不缺失Fc γ受体IIb）中分析TLR的功能。在野生型小鼠的整个肾脏和分离的肾小球中可检测到TLR 1至9和TLR 11 mRNA的表达，其中TLR 3和TLR 4具有最高的绝对表达水平。TLR1、2和4在TSLP转基因小鼠中增加，在TSLP转基因Fc γ RIIb缺陷小鼠中甚至更高。TLR5至9和11在TSLP转基因和TSLP转基因Fc γ RIIb缺陷小鼠中上调至相似程度。肾炎肾小球中TLR 4蛋白定位于足细胞的免疫组化研究。培养的足细胞也表达TLR4，TLR4特异性配体的刺激导致趋化因子的显著诱导;这通过用siRNA特异性敲低TLR4而减少。纤维蛋白原，一种潜在的内源性TLR4配体，显示诱导类似的趋化因子谱。总之，研究表明TLR 4由足细胞组成性表达，并在MPGN中上调，它可能通过调节趋化因子的表达来介导肾小球损伤;因此，TLR 4可能将足细胞与先天免疫系统连接起来，介导MPGN由免疫复合物沉积引发。
Toll-like receptors (TLR) classically recognize pathogen-associated danger signals but are also activated via endogenous ligands. For evaluation of their role in inflammatory kidney disease, the function of TLR was analyzed in two mouse models of cryoglobulinemic membranoproliferative glomerulonephritis (MPGN; mice transgenic for thymic stromal lymphopoietin [TSLP] with or without deletion of the Fc gamma receptor IIb). Expression of TLR1 through 9 and TLR1 1 mRNA was detectable in whole kidneys and in isolated glomeruli of wild-type mice, with TLR3 and TLR4 having the highest absolute levels of expression. TLR1, 2, and 4 were increased in TSLP transgenic mice and even higher in TSLP transgenic Fc gamma RIIb-deficient mice. TLR5 through 9 and 11 were upregulated to similar degrees in TSLP transgenic and TSLP transgenic Fc gamma RIIb-deficient mice. Immunohistochemical studies of nephritic glomeruli localized TLR4 protein to podocytes. Cultured podocytes also expressed TLR4, and stimulation with TLR4-specific ligands resulted in a marked induction of chemokines; this was reduced by specific knockdown of TLR4 with siRNA. Fibrinogen, a potential endogenous TLR4 ligand, was shown to induce a similar profile of chemokines. In conclusion, it was demonstrated that TLR4 is constitutively expressed by podocytes and is upregulated in MPGN, where it may mediate glomerular injury by modulating expression of chemokines; therefore, TLR4 may link podocytes with the innate immune system to mediate MPGN triggered by the deposition of immune complexes.