*Purpose: Hepatic ischemia-reperfusion injury (IRI) represents a major risk factor of 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 warm hepatic IRI. Here, we used a clinically relevant mouse model of hepatic cold storage followed by OLT to analyze the role of recipient-specific TIM4 signaling in IR-stressed OLT.

*Methods: WT liver grafts after 18h of cold storage were transplanted to groups of WT or TIM4-deficient (TIM4-KO) recipients; liver graft/blood samples were collected at 6h/24h after reperfusion. HMGB1-enriched liver flush (LF) was collected by infusing cold-stored WT livers. Bone marrow-derived neutrophil/macrophage (BMM) cultures from WT vs. TIM4-KO donors were stimulated with LPS/LF.

*Results: In contrast to WT>WT OLT, recipient TIM4 deficiency (WT>TIM4-KO) resulted in: 1/ increased sALT (6676±649 vs 4563±681 IU/L) levels at 6h after reperfusion (n=9/11, p<0.05); 2/ sustained elevations of sALT (4802±1086 vs 2740 ±834 IU/L) levels at 24h after OLT (n=10/4, p<0.05); 3/ augmented Suzuki's histological grading of IRI (6.7±0.5 vs 5.2±0.6, p<0.05, Fig. 1); 4/ higher frequency of TUNEL+ cells (p<0.05); 5/ enhanced macrophage/neutrophil OLT infiltration (p<0.05); 6/ increased mRNA levels coding for MCP1/CXCL1/CXCL2/CXCL10. Importantly, disruption of TIM4 signaling at the recipient site was highly pathogenic in vivo and curtailed the survival benefit in IR-stressed OLT (2-weeks: 0% vs 30%, n=16/10, p<0.001, Fig. 2). In parallel, TIM4 disruption in LPS/LF-activated BMDMs in vitro: 1/ augmented MCP1 mRNA levels, while inhibiting immunoregulatory PD1; and 2/ strongly enhanced mRNA levels coding for CXCL1/CXCL2.

*Conclusions: Cytodestructive TIM4-deficient phenotype triggered enhanced pro-inflammatory gene expression profile in bone marrow-derived macrophage/neutrophil cultures. By demonstrating unexpected requirement for TIM4 in hepatoprotection, this study highlights putative homeostatic in vivo function of recipient TIM4 signaling in controlling IR-stressed OLT.

« Back to 2019 American Transplant Congress