CXCL12-CXCR4-Mediated Chemotaxis is a Potential Mechanism for Monocyte Recruitment in Ischemia-Reperfusion Injury in Orthotopic Liver Transplant Patients

A. Q. Terry¹, R. A. Sosa¹, B. V. Naini¹, V. Groysberg¹, F. M. Kaldas², R. W. Busuttil², D. Gjertson¹, J. Kupiec-Weglinski², E. F. Reed¹

¹Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA, ²Surgery, University of California, Los Angeles, Los Angeles, CA

Meeting: 2019 American Transplant Congress

Abstract number: D250

Keywords: Inflammation, Mononuclear leukocytes, Portal veins, Risk factors

Session Information

Session Name: Poster Session D: Non-Organ Specific:Organ Preservation/Ischemia Reperfusion Injury

Session Type: Poster Session

Date: Tuesday, June 4, 2019

Session Time: 6:00pm-7:00pm

Presentation Time: 6:00pm-7:00pm

Location: Hall C & D

*Purpose: Ischemia-reperfusion injury (IRI) elicits cellular damage which lowers allograft survival in orthotopic liver transplant (OLT) patients. Damage-associated molecular patterns, such as high-mobility group box 1 (HMGB1), are released from injured hepatocytes during IRI which can recruit and/or activate the innate immune system. HMGB1 increases the CXCR4-mediated chemotaxis of myeloid cells by binding CXCR4’s canonical ligand, CXCL12. Post-reperfusion biopsies used to diagnose patients with IRI show increased myeloid infiltration in IRI+ patients compared to IRI- patients. Therefore, we hypothesized that elevations in HMGB1 and/or CXCL12 in IRI+ patient blood after reperfusion of the donor liver contributes to IRI via monocyte recruitment to the liver.

*Methods: HMGB1 and CXCL12 levels in pre- (portal vein; PV) and post-reperfusion (liver flush; LF) portal plasma from IRI+ (n=17) and IRI- (n=17) OLT patients were measured by ELISA. Third-party healthy donor monocytes were treated with LF from IRI- (n=12) and IRI+ (n=11) patients and CXCR4 expression on monocyte subpopulations was measured.

*Results: Mean HMGB1 levels in PV and LF and mean CXCL12 levels in PV showed no significant difference between IRI+ and IRI- patients. However, mean CXCL12 in LF samples was significantly higher in IRI+ versus IRI- patients (2228±468.9 pg/ml vs 1166±205.4 pg/ml, p<0.05). There was also a significant decrease of CXCL12 between PV and LF samples in IRI- versus IRI+ patients (mean decrease of 2587±438.3 pg/ml vs 1100±488 pg/ml, p<0.05). Interestingly, IRI+ LF induced higher expression of CXCR4 on the intermediate monocyte subpopulation (CD14⁺⁺CD16⁺; chronic inflammatory) of third-party healthy donor monocytes compared to IRI- LF.

*Conclusions: These data suggest that increased CXCL12, but not HMGB1, in post-reperfusion portal plasma increases the risk of IRI. Additionally, the larger decrease in CXCL12 between each IRI- patient’s PV and LF samples compared to the decrease between each IRI+ patient’s PV and LF samples suggests that CXCL12 sequestration and/or expression mechanisms might differ between IRI+ and IRI- patients. Further, the ability of IRI+ LF to cause higher expression of CXCR4 on the intermediate monocytes compared to IRI- LF suggests that IRI+ patients are more likely to have chronic-inflammatory monocytes recruited to the graft. Taken together, our data implicate the CXCL12-CXCR4 axis as a driving mechanism for monocyte recruitment in liver IRI. This recruitment pathway may provide therapeutic targets for improving OLT outcomes in the future.

To cite this abstract in AMA style:

Terry AQ, Sosa RA, Naini BV, Groysberg V, Kaldas FM, Busuttil RW, Gjertson D, Kupiec-Weglinski J, Reed EF. CXCL12-CXCR4-Mediated Chemotaxis is a Potential Mechanism for Monocyte Recruitment in Ischemia-Reperfusion Injury in Orthotopic Liver Transplant Patients [abstract]. Am J Transplant. 2019; 19 (suppl 3). https://atcmeetingabstracts.com/abstract/cxcl12-cxcr4-mediated-chemotaxis-is-a-potential-mechanism-for-monocyte-recruitment-in-ischemia-reperfusion-injury-in-orthotopic-liver-transplant-patients/. Accessed May 16, 2025.

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