Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon gamma-mediated pathway

Hidenobu Kojima; Thomas A Morinelli; Yue Wang; Jackson L Chin; Aaron S Meyer; Yi-Chu Kao; Kentaro Kadono; Siyuan Yao; Taylor Torgerson; Kenneth J Dery; Adil Bhat; Elaine F Reed; Fady M Kaldas; Dirk J van der Windt; Douglas G Farmer; Jerzy W Kupiec-Weglinski; Yuan Zhai

doi:10.1016/j.ajt.2024.11.035

Group 1 innate lymphoid cells protect liver transplants from ischemia-reperfusion injury via an interferon gamma-mediated pathway

Am J Transplant. 2024 Dec 28:S1600-6135(24)00793-7. doi: 10.1016/j.ajt.2024.11.035. Online ahead of print.

Authors

Hidenobu Kojima¹, Thomas A Morinelli², Yue Wang², Jackson L Chin³, Aaron S Meyer³, Yi-Chu Kao², Kentaro Kadono¹, Siyuan Yao¹, Taylor Torgerson¹, Kenneth J Dery¹, Adil Bhat⁴, Elaine F Reed⁴, Fady M Kaldas¹, Dirk J van der Windt², Douglas G Farmer¹, Jerzy W Kupiec-Weglinski¹, Yuan Zhai⁵

Affiliations

¹ The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
² Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA.
³ Department of Bioengineering, University of California, Los Angeles, Los Angeles, California, USA.
⁴ Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
⁵ The Dumont-UCLA Transplantation Center, Department of Surgery, Division of Liver and Pancreas Transplantation, David Geffen School of Medicine at UCLA, Los Angeles, California, USA; Department of Surgery, Medical University of South Carolina, Charleston, South Carolina, USA. Electronic address: zhaiy@musc.edu.

PMID: 39736469
DOI: 10.1016/j.ajt.2024.11.035

Abstract

As important immune regulatory cells, whether innate lymphoid cells (ILCs) are involved in liver transplantation (LT) remains unclear. In a murine orthotopic LT model, we dissected roles of ILCs in liver ischemia-reperfusion injury (IRI). Wild-type (WT) grafts suffered significantly higher IRI in Rag2-γc double knockout (DKO) than Rag2 knockout (KO) recipients, in association with downregulation of group 1 ILCs genes, including interferon gamma. Antibody-mediated ILC depletion or interferon gamma neutralization in Rag2 KO recipients increased, while interferon gamma treatment in DKO recipients reduced, liver graft injuries. At the donor side, grafts from DKO mice or anti-NK1.1-treated WT mice suffered significantly higher IRI, while grafts treated with interferon gamma during cold preservation decreased IRI. Thus, both recipient and donor group 1 ILCs protect liver grafts from IRI. Low-dose interferon gamma upregulated c-FLIP expression in vitro and in vivo and protected hepatocytes from inflammatory cell death. In human liver graft biopsies, single-cell RNA-sequencing analysis revealed group 1 ILCs produce interferon gamma. The c-FLIP levels were positively correlated with interferon gamma in pretransplant biopsies. Grafts with higher c-FLIP were associated with lower caspase-8 activation, IRI gradings, and frequency of early allograft dysfunction post-LT. Our study reveals a novel interferon gamma-mediated cytoprotective role of group 1 ILCs in LT.

Keywords: acute liver injury; apoptosis; innate lymphoid cell; interferon gamma; liver transplantation.