Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection
Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection
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DOI：
10.1002/hep.31499
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发表时间：
2021-03-30
期刊：
影响因子：
13.5
通讯作者：
Bhat, Mamatha
中科院分区：
文献类型：
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作者：
Deppermann, Carsten;Peiseler, Moritz;Bhat, Mamatha
枯否细胞（Kupffer cells，KCs）是肝脏血管内的吞噬细胞，对捕获和杀灭细菌具有重要作用。钙调神经磷酸酶/活化T细胞核因子（NFAT）抑制剂（CNI）如他克莫司用于预防实体器官移植受者的排斥反应。虽然他们对淋巴细胞的影响已被广泛研究，有有限的实验数据，如果和如何CNIS形状先天免疫，以及是否这有助于观察到的感染率较高的患者服用CNIs.Approach和结果在这里，我们调查了他克莫司治疗对先天免疫的影响，更具体地说，对库普弗细胞（KCs）的能力，以对抗感染。对2,700例以上肝移植受者数据的回顾性分析显示，服用钙调磷酸酶抑制剂如他克莫司显著增加了金黄色葡萄球菌感染的可能性。采用小鼠急性耐甲氧西林沙门氏菌模型。在金黄色葡萄球菌（MRSA）菌血症中，大多数细菌被隔离在肝脏中，并且我们发现细菌更可能在他克莫司治疗的小鼠中传播并杀死宿主。利用成像技术，我们揭示了这一观察结果背后的机制：在他克莫司治疗的动物中，KC捕获、吞噬和破坏细菌的能力降低。此外，在受感染KC的基因表达分析中，髓样细胞表达的触发受体1（TREM 1）途径是他克莫司治疗后下调最显著的途径。TREM 1抑制同样抑制KC细菌捕获。中性粒细胞的TREM 1水平以及感染后的总体中性粒细胞反应不受他克莫司treatment.Conclusions的影响，我们的研究结果表明，他克莫司治疗有显着的影响，直接对KC和TREM 1，从而损害了他们抵御感染的能力。
Background and Aims Kupffer cells (KCs) are the resident intravascular phagocyte population of the liver and critical to the capture and killing of bacteria. Calcineurin/nuclear factor of activated T cells (NFAT) inhibitors (CNIs) such as tacrolimus are used to prevent rejection in solid organ transplant recipients. Although their effect on lymphocytes has been studied extensively, there are limited experimental data about if and how CNIs shape innate immunity, and whether this contributes to the higher rates of infection observed in patients taking CNIs.Approach and Results Here, we investigated the impact of tacrolimus treatment on innate immunity and, more specifically, on the capability of Kupffer cells (KCs) to fight infections. Retrospective analysis of data of >2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of Staphylococcus aureus infection. Using a mouse model of acute methicillin-resistant S. aureus (MRSA) bacteremia, most bacteria were sequestered in the liver and we found that bacteria were more likely to disseminate and kill the host in tacrolimus-treated mice. Using imaging, we unveiled the mechanism underlying this observation: the reduced capability of KCs to capture, phagocytose, and destroy bacteria in tacrolimus-treated animals. Furthermore, in a gene expression analysis of infected KCs, the triggering receptor expressed on myeloid cells 1 (TREM1) pathway was the one with the most significant down-regulation after tacrolimus treatment. TREM1 inhibition likewise inhibited KC bacteria capture. TREM1 levels on neutrophils as well as the overall neutrophil response after infection were unaffected by tacrolimus treatment.Conclusions Our results indicate that tacrolimus treatment has a significant impact directly on KCs and on TREM1, thereby compromising their capacity to fend off infections.