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

Kojiro Nakamura; Shoichi Kageyama; Fady M. Kaldas; Hirofumi Hirao; Takahiro Ito; Kentaro Kadono; Kenneth J. Dery; Hidenobu Kojima; David W. Gjertson; Rebecca A. Sosa; Maciej Kujawski; Ronald W. Busuttil; Elaine F. Reed; Jerzy W. Kupiec-Weglinski

doi:10.1172/JCI133142

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

Kojiro Nakamura,¹ Shoichi Kageyama,¹ Fady M. Kaldas,² Hirofumi Hirao,² Takahiro Ito,² Kentaro Kadono,² Kenneth J. Dery,² Hidenobu Kojima,² David W. Gjertson,⁴ Rebecca A. Sosa,⁵ Maciej Kujawski,⁶ Ronald W. Busuttil,² Elaine F. Reed,⁵ and Jerzy W. Kupiec-Weglinski²

Published February 6, 2020 - More info

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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 BMDM cultures. Although hepatic CC1 deficiency augmented cold stress-triggered ASK1/p-p38 upregulation, adjunctive ASK1 inhibition alleviated IRI/improved OLT survival by suppressing p-p38 upregulation, ROS induction/HMGB1 translocation (CC1-KO>WT); while ASK1 silencing (siRNA) promoted cytoprotection in cold-stressed and damage-prone CC1-deficient hepatocyte cultures. Consistent with mouse data, CEACAM1 expression in sixty human donor liver biopsies correlated negatively with activation of ASK1/p-p38 axis; while low-CC1 levels associated with increased ROS/HMGB1 translocation, enhanced innate/adaptive immune responses and inferior early OLT function. Notably, reduced donor liver CEACAM1 expression was identified as one of independent predictors for EAD in human OLT patients. Thus, as a checkpoint regulator of IR-stress/sterile inflammation, CEACAM1 may be considered as a denominator of donor hepatic tissue quality, and a target for therapeutic modulation in OLT recipients.

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

Kojiro Nakamura,¹ Shoichi Kageyama,¹ Fady M. Kaldas,² Hirofumi Hirao,² Takahiro Ito,² Kentaro Kadono,² Kenneth J. Dery,² Hidenobu Kojima,² David W. Gjertson,⁴ Rebecca A. Sosa,⁵ Maciej Kujawski,⁶ Ronald W. Busuttil,² Elaine F. Reed,⁵ and Jerzy W. Kupiec-Weglinski²

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

Kojiro Nakamura,1 Shoichi Kageyama,1 Fady M. Kaldas,2 Hirofumi Hirao,2 Takahiro Ito,2 Kentaro Kadono,2 Kenneth J. Dery,2 Hidenobu Kojima,2 David W. Gjertson,4 Rebecca A. Sosa,5 Maciej Kujawski,6 Ronald W. Busuttil,2 Elaine F. Reed,5 and Jerzy W. Kupiec-Weglinski2

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Kojiro Nakamura,¹ Shoichi Kageyama,¹ Fady M. Kaldas,² Hirofumi Hirao,² Takahiro Ito,² Kentaro Kadono,² Kenneth J. Dery,² Hidenobu Kojima,² David W. Gjertson,⁴ Rebecca A. Sosa,⁵ Maciej Kujawski,⁶ Ronald W. Busuttil,² Elaine F. Reed,⁵ and Jerzy W. Kupiec-Weglinski²