Hepatic CEACAM1 expression indicates donor liver quality and prevents early transplantation injury

Bomi Lee, Julia Z. Adamska, Hong Namkoong, Melena D. Bellin, Josh Wilhelm, Gregory L. Szot, David M. Louis, Mark M. Davis, Stephen J. Pandol, Aida Habtezion

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Although CEACAM1 (CC1) glycoprotein resides at the interface of immune liver injury and metabolic homeostasis, its role in orthotopic liver transplantation (OLT) remains elusive. We aimed to determine whether/how CEACAM1 signaling may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. In the mouse, donor liver CC1 null mutation augmented IRI-OLT (CC1-KO→WT) by enhancing ROS expression and HMGB1 translocation during cold storage, data supported by in vitro studies where hepatic flush from CC1-deficient livers enhanced macrophage activation in bone marrow-derived macrophage cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI and improved OLT survival by suppressing p-p38 upregulation, ROS induction, and HMGB1 translocation (CC1-KO→WT), whereas ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in 60 human donor liver biopsies correlated negatively with activation of the ASK1/p-p38 axis, whereas low CC1 levels associated with increased ROS and HMGB1 translocation, enhanced innate and adaptive immune responses, and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of the independent predictors for early allograft dysfunction (EAD) in human OLT patients. Thus, as a checkpoint regulator of IR stress and sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

Original languageEnglish (US)
Pages (from-to)2705-2711
Number of pages16
JournalJournal of Clinical Investigation
Volume130
Issue number5
DOIs
StatePublished - May 1 2020

Bibliographical note

Funding Information:
This study was supported in part by NIH grant DK105263 (to AH), a National Pancreas Foundation (NPF) 2019 Research Grant (BL), and the HHMI (MMD, DML). We thank our collaborators, patients, and donors for providing precious human pancreas tissues and the Habtezion laboratory members for their helpful comments.

Publisher Copyright:
Copyright: © 2020, American Society for Clinical Investigation.

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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