Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.
Macrophage depletion ameliorates nephritis induced by pathogenic antibodies.
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DOI：
10.1016/j.jaut.2014.11.007
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发表时间：
2015-02
影响因子：
12.8
通讯作者：
Putterman C
中科院分区：
文献类型：
--
作者：
Chalmers SA;Chitu V;Herlitz LC;Sahu R;Stanley ER;Putterman C
肾脏受累影响40-60%的狼疮患者，是造成显著发病率和死亡率的原因。利用耗竭方法，一些研究表明巨噬细胞可能在狼疮肾炎的发病机制中起关键作用。然而，巨噬细胞消耗的“脱靶”效应，如造血功能改变或自身抗体产生增强，阻碍了结论性关系的确定。在这项研究中，我们研究了巨噬细胞在接受兔抗肾小球抗体或肾毒性血清（NTS）的小鼠中的作用，这是一种模拟小鼠和人类狼疮性肾炎中免疫复合物介导疾病的实验模型。GW2580是一种集落刺激因子-1 （CSF-1）受体激酶的选择性抑制剂，用于巨噬细胞的清除。我们发现gw2580处理的NTS挑战小鼠没有出现与对照组处理的NTS挑战小鼠相比的蛋白尿、血清肌酐或血清尿素水平升高。NTS刺激小鼠的肾脏炎症细胞因子（包括RANTES、IP-10、VCAM-1和iNOS）的表达显著增加，而gw2580处理小鼠则不受这些与LN相关的炎症细胞因子的强烈表达的影响。巨噬细胞相关基因表达的定量、肾单细胞悬液的流式细胞术分析和免疫荧光染色证实了gw2580处理小鼠中巨噬细胞的消耗，特别是肾小球内的巨噬细胞。我们的研究结果强烈暗示巨噬细胞在病原抗体介导的免疫性肾小球肾炎的发展中具有特异性和必要的作用，并支持巨噬细胞靶向治疗狼疮肾炎的方法的发展。
Kidney involvement affects 40–60% of patients with lupus and is responsible for significant morbidity and mortality. Using depletion approaches, several studies have suggested that macrophages may play a key role in the pathogenesis of lupus nephritis. However, “off target” effects of macrophage depletion, such as altered hematopoiesis or enhanced autoantibody production, impeded the determination of a conclusive relationship. In this study, we investigated the role of macrophages in mice receiving rabbit anti-glomerular antibodies, or nephrotoxic serum (NTS), an experimental model which closely mimics the immune complex mediated disease seen in murine and human lupus nephritis. GW2580, a selective inhibitor of the colony stimulating factor-1 (CSF-1) receptor kinase, was used for macrophage depletion. We found that GW2580-treated, NTS challenged mice did not develop the increased levels of proteinuria, serum creatinine, or serum urea seen in control-treated, NTS challenged mice. NTS challenged mice exhibited significantly increased kidney expression of inflammatory cytokines including RANTES, IP-10, VCAM-1 and iNOS, whereas GW2580-treated mice were protected from the robust expression of these inflammatory cytokines that are associated with LN. Quantification of macrophage related gene expression, flow cytometry analysis of kidney single cell suspensions, and immunofluorescence staining confirmed the depletion of macrophages in GW2580-treated mice, specifically within renal glomeruli. Our results strongly implicate a specific and necessary role for macrophages in the development of immune glomerulonephritis mediated by pathogenic antibodies, and support the development of macrophage targeting approaches for the treatment of lupus nephritis.
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影响因子：
7.8
作者：
Byrne, P V;Guilbert, L J;Stanley, E R
通讯作者：
Stanley, E R
DOI：
10.1124/jpet.107.129429
发表时间：
2008-07-01
影响因子：
3.5
作者：
Conway, James G.;Pink, Heather;Brodie, Thomas A.
通讯作者：
Brodie, Thomas A.
影响因子：
20.3
作者：
Dai, XM;Ryan, GR;Stanley, ER
通讯作者：
Stanley, ER
影响因子：
5
作者：
Han, Yingjie;Ma, Frank Y.;Nikolic-Paterson, David J.
通讯作者：
Nikolic-Paterson, David J.
影响因子：
3.3
作者：
Kim, SH;Kang, YJ;Lee, WH
通讯作者：
Lee, WH