Spatiotemporal expression of chemokines and chemokine receptors in experimental anti-myeloperoxidase antibody-mediated glomerulonephritis
Spatiotemporal expression of chemokines and chemokine receptors in experimental anti-myeloperoxidase antibody-mediated glomerulonephritis
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DOI：
10.1111/j.1365-2249.2009.03993.x
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发表时间：
2009-10-01
影响因子：
4.6
通讯作者：
Heeringa, P.
中科院分区：
文献类型：
--
作者：
van der Veen, B. S.;Petersen, A. H.;Heeringa, P.
髓过氧化物酶(MPO)-抗中性粒细胞胞浆自身抗体(ANCA)-相关坏死性新月形肾小球肾炎（NCGN）以白细胞浸润丰富为特征。趋化因子是参与受体介导的白细胞募集的趋化细胞因子。我们的目的是分析抗mpo介导的NCGN中趋化因子和趋化因子受体的时空基因表达，以寻找干预白细胞内流的潜在靶点。用抗mpo免疫球蛋白（Ig）G和脂多糖共给药诱导小鼠NCGN。在NCGN诱导后1天和7天，分析全肾裂解物、激光显微解剖肾小球和小管间质组织中趋化因子和趋化因子受体的mRNA表达水平。在抗mpo介导的NCGN中，在第1天（趋化因子CCL3、5；CXCL2、5、13；受体CXCR2）和第7天(趋化因子CCL2、5、7、8、17、20；CXCL1、2、5、10；受体ccr2,8；残雪(3)CR1)。大多数趋化因子和受体在肾小球中的表达水平高于小管间质。由于CXCR2在第1天的时间诱导，我们假设CXCR2是治疗抗mpo诱导的NCGN的潜在靶点。在NCGN诱导前使用山羊抗CXCR2血清抑制CXCR2可增加肾小球中性粒细胞内流，但不影响新月形成和蛋白尿。综上所述，抗mpo NCGN中各种趋化因子和趋化因子受体的表达水平升高，且在肾小球中表达尤为明显。这些趋化因子和受体可作为治疗的潜在靶点。单个靶点CXCR2的抑制不会减弱抗mpo NCGN。为了避免冗余，组合干预可能是必要的。
P>Myeloperoxidase (MPO)-anti-neutrophil cytoplasmic autoantibody (ANCA)-associated necrotizing crescentic glomerulonephritis (NCGN) is characterized by abundant leucocyte infiltration. Chemokines are chemotactic cytokines involved in receptor-mediated recruitment of leucocytes. Our objective was to analyse spatiotemporal gene expression of chemokines and chemokine receptors in anti-MPO-mediated NCGN, to find potential targets for intervening with leucocyte influx. NCGN was induced in mice by co-administration of anti-MPO immunoglobulin (Ig)G and lipopolysaccharide. mRNA expression levels of chemokines and chemokine receptors were analysed in whole kidney lysates as well as in laser microdissected glomeruli and tubulo-interstitial tissue 1 and 7 day(s) after NCGN induction. Several chemokines and chemokine receptors were induced or up-regulated in anti-MPO-mediated NCGN, both on day 1 (chemokines CCL3, 5; CXCL2, 5, 13; receptor CXCR2) and on day 7 (chemokines CCL2, 5, 7, 8, 17, 20; CXCL1, 2, 5, 10; CX(3)CL1; receptors CCR2, 8; CX(3)CR1). The expression levels of most chemokines and receptors were higher in glomeruli than in the tubulo-interstitium. Because of the temporal induction of CXCR2 on day 1, we hypothesized CXCR2 as a potential target for treatment in anti-MPO-induced NCGN. Inhibition of CXCR2 using a goat-anti-CXCR2 serum prior to NCGN induction increased glomerular neutrophil influx but did not affect crescent formation and albuminuria. In conclusion, expression levels of various chemokines and chemokine receptors were increased in anti-MPO NCGN, and expressed particularly in glomeruli. These chemokines and receptors may serve as potential targets for treatment. Inhibition of a single target, CXCR2, did not attenuate anti-MPO NCGN. Combinatorial interventions may be necessary to avoid redundancy.