Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Renal Transplant Unit, Department of Internal Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
Sci Rep. 2019 Jan 14;9(1):106. doi: 10.1038/s41598-018-37482-x.
Calcineurin inhibitor Tacrolimus, is a potent immunosuppressive drug widely used in order to prevent acute graft rejection. Urinary tract infection (UTI) is the most frequent infectious complication in renal transplant patients and long-term use of Tacrolimus might be involved in higher susceptibility to bacterial infections. It remains largely unknown how Tacrolimus affects the host innate immune response against lower and upper UTI. To address this issue, we used experimental UTI model by intravesical inoculation of uropathogenic E.coli in female wild-type mice pre-treated with Tacrolimus or solvent (CTR). We found that Tacrolimus pre-treated mice displayed higher bacterial loads (cystitis, pyelonephritis and bacteremia) than CTR mice. Granulocytes from Tacrolimus pre-treated mice phagocytized less E. coli, released less MPO and expressed decreased levels of CXCR2 receptor upon infection. Moreover, Tacrolimus reduced TLR5 expression in bladder macrophages during UTI. This immunosuppressive state can be explained by the upregulation of TLR-signaling negative regulators (A20, ATF3, IRAK-M and SOCS1) and parallel downregulation of TLR5 as observed in Tacrolimus treated granulocytes and macrophages. We conclude that Tacrolimus impairs host innate immune responses against UTI.
钙调磷酸酶抑制剂他克莫司是一种强效免疫抑制剂，广泛用于预防急性移植物排斥反应。尿路感染（UTI）是肾移植患者最常见的感染性并发症，而长期使用他克莫司可能与更高的细菌感染易感性有关。他克莫司如何影响宿主对下尿路感染和上尿路感染的固有免疫反应，在很大程度上仍不清楚。为了解决这个问题，我们使用了经膀胱接种尿路致病性大肠杆菌的实验性尿路感染模型，在该模型中，雌性野生型小鼠预先用他克莫司或溶剂（CTR）处理。我们发现，与 CTR 小鼠相比，预先用他克莫司处理的小鼠显示出更高的细菌负荷（膀胱炎、肾盂肾炎和菌血症）。感染时，预先用他克莫司处理的小鼠中性粒细胞吞噬的大肠杆菌减少，释放的髓过氧化物酶减少，表达的 CXCR2 受体水平降低。此外，在尿路感染期间，他克莫司下调了膀胱巨噬细胞中的 TLR5 表达。这种免疫抑制状态可以通过 TLR 信号负调节因子（A20、ATF3、IRAK-M 和 SOCS1）的上调以及在他克莫司处理的粒细胞和巨噬细胞中观察到的 TLR5 的平行下调来解释。我们得出结论，他克莫司损害了宿主对尿路感染的固有免疫反应。
