CCR2‐dependent Gr1high monocytes promote kidney injury in shiga toxin‐induced hemolytic uremic syndrome in mice
CCR2‐dependent Gr1high monocytes promote kidney injury in shiga toxin‐induced hemolytic uremic syndrome in mice
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DOI：
10.1002/eji.201747138
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发表时间：
2018-02
影响因子：
5.4
通讯作者：
Judith-Mira Pohl;J. Volke;S. Thiebes;Alexandra Brenzel;K. Fuchs;N. Beziere;W. Ehrlichmann;B. Pichler;A. Squire;F. Gueler;D. Engel
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文献类型：
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作者：
Judith-Mira Pohl;J. Volke;S. Thiebes;Alexandra Brenzel;K. Fuchs;N. Beziere;W. Ehrlichmann;B. Pichler;A. Squire;F. Gueler;D. Engel
溶血性尿毒综合征（HUS）是一种由产滋贺毒素的大肠杆菌引起的危及生命的肾脏疾病。已观察到单核细胞区室和CCR 2结合趋化因子的重大变化。然而，CCR 2依赖性Gr 1high单核细胞的具体作用尚不清楚。为了研究这些单核细胞在HUS期间的影响，我们将LPS和滋贺毒素的组合注射到小鼠中。我们观察到在滋贺毒素/LPS-注射后肾功能受损和CCR 2结合趋化因子CCL 2水平升高，因此表明Gr 1高单核细胞浸润到肾脏中。事实上，在HUS诱导后一天，Gr 1high单核细胞的数量强烈增加。此外，这些细胞表达高水平的CD 11b，表明进入组织后活化。无创PET‐MR成像显示肾损伤主要发生在肾皮质，这种损伤与Gr 1高单核细胞的检测一致。Ccr 2缺陷动物中缺乏Gr 1high单核细胞可降低中性粒细胞明胶酶相关脂质运载蛋白和血尿素氮水平。此外，Ccr 2缺陷动物的存活率显著提高。总之，这项研究表明，CCR 2依赖性Gr 1high单核细胞有助于HUS期间的肾损伤，靶向这些细胞在这种疾病中是有益的。
The hemolytic uremic syndrome (HUS) is a life‐threatening disease of the kidney that is induced by shiga toxin‐producing E.coli. Major changes in the monocytic compartment and in CCR2‐binding chemokines have been observed. However, the specific contribution of CCR2‐dependent Gr1high monocytes is unknown. To investigate the impact of these monocytes during HUS, we injected a combination of LPS and shiga toxin into mice. We observed an impaired kidney function and elevated levels of the CCR2‐binding chemokine CCL2 after shiga toxin/LPS‐ injection, thus suggesting Gr1high monocyte infiltration into the kidney. Indeed, the number of Gr1high monocytes was strongly increased one day after HUS induction. Moreover, these cells expressed high levels of CD11b suggesting activation after tissue entry. Non‐invasive PET‐MR imaging revealed kidney injury mainly in the kidney cortex and this damage coincided with the detection of Gr1high monocytes. Lack of Gr1high monocytes in Ccr2‐deficient animals reduced neutrophil gelatinase‐associated lipocalin and blood urea nitrogen levels. Moreover, the survival of Ccr2‐deficient animals was significantly improved. Conclusively, this study demonstrates that CCR2‐dependent Gr1high monocytes contribute to the kidney injury during HUS and targeting these cells is beneficial during this disease.