CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis
CXCL10 induces the recruitment of monocyte-derived macrophages into kidney, which aggravate puromycin aminonucleoside nephrosis
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DOI：
10.1111/cei.12579
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发表时间：
2015-05-01
影响因子：
4.6
通讯作者：
Partida-Sanchez, S.
中科院分区：
文献类型：
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作者：
Petrovic-Djergovic, D.;Popovic, M.;Partida-Sanchez, S.
在嘌呤霉素氨基核苷诱导的大鼠肾病综合征模型（PAN - NS）中，单核细胞衍生的巨噬细胞向肾脏迁移的机制以及这种浸润的意义在很大程度上仍然未知。CXCL10是一种在许多1型辅助性T细胞（Th1）炎症性疾病中分泌的趋化因子，在单核细胞和活化T细胞的迁移中发挥重要作用。我们假设在PAN - NS期间循环干扰素（IFN）和肾小球肿瘤坏死因子（TNF）的诱导会刺激足细胞释放CXCL10，从而导致活化免疫细胞的浸润和更严重的肾小球损伤。我们发现，在Wistar大鼠PAN - NS的急性后期，血清IFN、肾小球Cxcl10 mRNA以及肾小球内和肾小球周围巨噬细胞浸润显著增加，但在缺乏功能性效应T淋巴细胞的裸鼠（Foxn1(rnu/rnu)）中则没有。Wistar大鼠也比裸鼠出现更明显的蛋白尿，而巨噬细胞耗竭可消除这种蛋白尿。用IFN和TNF刺激培养的足细胞可显著诱导Cxcl10 mRNA的表达和CXCL10的分泌。总之，这些数据支持我们的假设，即循环中IFN增加和肾小球TNF协同诱导足细胞产生和分泌CXCL10，吸引活化的巨噬细胞进入肾组织。该研究还表明，由Th1淋巴细胞分泌的IFN可能使促炎巨噬细胞活化，从而加重肾损伤。
The mechanism responsible for trafficking of monocyte-derived macrophages into kidney in the puromycin aminonucleoside model of nephrotic syndrome in rats (PAN-NS), and the significance of this infiltration, remain largely unknown. CXCL10, a chemokine secreted in many T helper type 1 (Th1) inflammatory diseases, exhibits important roles in trafficking of monocytes and activated T cells. We hypothesized that induction of circulating interferon (IFN)- and glomerular tumour necrosis factor (TNF)- during PAN-NS would stimulate the release of CXCL10 by podocytes, leading to infiltration of activated immune cells and greater glomerular injury. We found that serum IFN-, glomerular Cxcl10mRNA and intra- and peri-glomerular macrophage infiltration were induced strongly during the late acute phase of PAN-NS in Wistar rats, but not in nude (Foxn1(rnu/rnu)) rats lacking functional effector T lymphocytes. Wistar rats also developed significantly greater proteinuria than nude rats, which could be abolished by macrophage depletion. Stimulation of cultured podocytes with both IFN- and TNF- markedly induced the expression of Cxcl10mRNA and CXCL10 secretion. Together, these data support our hypothesis that increased circulating IFN- and glomerular TNF- induce synergistically the production and secretion of CXCL10 by podocytes, attracting activated macrophages into kidney tissue. The study also suggests that IFN-, secreted from Th1 lymphocytes, may prime proinflammatory macrophages that consequently aggravate renal injury.