{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T15:03:49Z","timestamp":1789830229241,"version":"4.0.1"},"reference-count":32,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"5","license":[{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,3,30]],"date-time":"2021-03-30T00:00:00Z","timestamp":1617062400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2021,5]]},"abstract":"<jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>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 &gt;2,700 liver transplant recipients showed that taking calcineurin inhibitors such as tacrolimus significantly increased the likelihood of <jats:italic toggle=\"yes\">Staphylococcus aureus<\/jats:italic> infection. Using a mouse model of acute methicillin\u2010resistant <jats:italic toggle=\"yes\">S. aureus<\/jats:italic> (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\u2010treated mice. Using imaging, we unveiled the mechanism underlying this observation: the reduced capability of KCs to capture, phagocytose, and destroy bacteria in tacrolimus\u2010treated 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\u2010regulation 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our results indicate that tacrolimus treatment has a significant impact directly on KCs and on TREM1, thereby compromising their capacity to fend off infections.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.31499","type":"journal-article","created":{"date-parts":[[2020,8,6]],"date-time":"2020-08-06T19:21:17Z","timestamp":1596741677000},"page":"1967-1984","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":26,"title":["Tacrolimus Impairs Kupffer Cell Capacity to Control Bacteremia: Why Transplant Recipients Are Susceptible to Infection"],"prefix":"10.1097","volume":"73","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3740-8635","authenticated-orcid":false,"given":"Carsten","family":"Deppermann","sequence":"first","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"},{"name":"Institute of Clinical Chemistry and Laboratory Medicine,University Medical Center Hamburg\u2010Eppendorf,Hamburg,Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moritz","family":"Peiseler","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joel","family":"Zindel","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lori","family":"Zbytnuik","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Woo\u2010Yong","family":"Lee","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Pasini","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Baciu","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Matelski","sequence":"additional","affiliation":[{"name":"Biostatistics Research Unit,University Health Network,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deepali","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atul","family":"Humar","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bas","family":"Surewaard","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Kubes","sequence":"additional","affiliation":[{"name":"Snyder Institute for Chronic Diseases,University of Calgary,Calgary,AL,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamatha","family":"Bhat","sequence":"additional","affiliation":[{"name":"Department of Medicine,Multi\u2010Organ Transplant Program,Toronto General Hospital,Toronto,ON,Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,3,30]]},"reference":[{"key":"hep31499-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"996","DOI":"10.1038\/ni.2691","article-title":"Immune surveillance by the liver","volume":"14","year":"2013","journal-title":"Nat Immunol"},{"key":"hep31499-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"4643","DOI":"10.1172\/JCI127286","article-title":"Peritoneal GATA6+ macrophages function as a portal for Staphylococcus aureus dissemination","volume":"129","year":"2019","journal-title":"J Clin Invest"},{"key":"hep31499-bib-0003-20250824","first-page":"713","article-title":"Studies on bacteriemia. 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