Recipient TIM4+ Macrophage is a Central Hub for Metabolic Homeostasis in Liver Transplantation: From Mouse-to-Human
H. Hirao, K. Kadono, H. Kojima, K. J. Dery, D. G. Farmer, F. M. Kaldas, J. Kupiec-Weglinski
UCLA, Los Angeles, CA
Meeting: 2022 American Transplant Congress
Abstract number: 1314
Keywords: Metabolic complications
Topic: Basic Science » Basic Clinical Science » 18 - Immunometabolism
Session Information
Session Time: 7:00pm-8:00pm
Presentation Time: 7:00pm-8:00pm
Location: Hynes Halls C & D
*Purpose: Hepatic ischemia-reperfusion injury (IRI) is a major risk factor for early graft dysfunction and predisposes to rejection in orthotopic liver transplantation (OLT). Previous studies have reported on the pathogenic function of T-cell immunoglobulin mucin 4 (TIM4) in Kupffer cells in a mouse warm hepatic IRI model. However, little is known about the role of recipient TIM4 in OLT. Here, we used a clinically relevant mouse OLT to analyze the function of recipient-specific TIM4 in IRI-OLT.
*Methods: WT liver grafts (C57/BL6) after 18h of cold storage were transplanted to WT or TIM4-deficient (TIM4-KO) syngeneic recipients. Liver graft/blood samples were collected at 6h post-OLT. In the clinical arm, human hepatic biopsies obtained at 2h post-OLT (n=55) were screened for TIM4/pro-inflammatory phenotype (RT-PCR).
*Results: In contrast to WT>WT OLT, disruption of recipient TIM4 signaling (WT>TIM4-KO) resulted in: 1/ increased sALT (6676±649 vs 4563±681 IU/L) levels at 6h post-reperfusion (n=9/11, p<0.05); 2/ augmented Suzuki's histological grading of hepatic IRI (6.7±0.5 vs 5.2±0.6, p<0.05, Fig. 1); 3/ higher frequency of TUNEL+ cells (p<0.05); 4/ increased pro-inflammatory chemokine gene expression. Unexpectedly, disruption of TIM4 signaling at the recipient site curtailed the survival benefit seen otherwise in IR-stressed OLT (2-wk: 0% vs 30%, n=16/10 resp., p<0.001). Western blot analysis of OLTs showed enhanced expression of CD36, PPARγ (Peroxisome proliferator-activated receptor gamma), CHOP (C/EBP Homologous Protein) and ACSL4 (Acyl-CoA Synthetase Long Chain Family Member 4). Serum-free fatty acid level was significantly higher in TIM4-KO recipient group. These results suggest the key role of recipient TIM4 in the maintenance of metabolic homeostasis against IR-stress. In the clinical arm, TIM4 expression was positively correlated with serum AST levels at postoperative day 1. When divided into low (n=28) vs. high (n=27) TIM4 expression groups, TIM4 high human OLTs showed enhanced innate/adaptive immune activation (RT-PCR) and CHOP expression (Western blot).
*Conclusions: Cytodestructive TIM4-deficient recipient phenotype triggered enhanced pro-inflammatory gene expression program in experimental OLT. By demonstrating unexpected requirement for recipient TIM4 signaling in the mechanism of hepatoprotection, this study highlights putative metabolic homeostatic function of TIM4 in controlling IR-stress in OLT recipients.
To cite this abstract in AMA style:
Hirao H, Kadono K, Kojima H, Dery KJ, Farmer DG, Kaldas FM, Kupiec-Weglinski J. Recipient TIM4+ Macrophage is a Central Hub for Metabolic Homeostasis in Liver Transplantation: From Mouse-to-Human [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/recipient-tim4-macrophage-is-a-central-hub-for-metabolic-homeostasis-in-liver-transplantation-from-mouse-to-human/. Accessed November 3, 2024.« Back to 2022 American Transplant Congress