DAP12 and Its Triggering Co-Receptor TREM2 Play Key Roles in Regulation of Mouse and Human Liver DC Function and Control of Liver Ischemia-Reperfusion Injury
1Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
2Liver Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA
3Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Meeting: 2018 American Transplant Congress
Abstract number: 11
Session Information
Session Name: Concurrent Session: Antigen Presentation / Allorecognition / Dendritic Cells
Session Type: Concurrent Session
Date: Sunday, June 3, 2018
Session Time: 2:30pm-4:00pm
Presentation Time: 3:42pm-3:54pm
Location: Room 4C-3
Background: Liver interstitial dendritic cells (DCs) have been implicated in the control of liver ischemia/reperfusion injury (IRI) and in the induction of liver transplant tolerance. However, mechanisms underlying these regulatory functions of liver DCs remain unclear. We have shown previously that the transmembrane adaptor protein DNAX-activating protein of 12 kDa (DAP12) is a negative regulator of mouse liver DC maturation. In this study, we focused on the role of DAP12 and its associated triggering receptor, triggering receptor expressed on myeloid cells 2 (TREM2) in the regulation of both mouse and human liver DC function and the role of DAP12 in regulation of liver IRI.
Materials and Methods: siRNA was used for gene silencing in human liver DCs. T cell proliferation was determined by CFSE-MLR and cytokine production by cytokine bead array analysis. Liver warm IRI was induced in DAP12-/- or WT mice by 1 hour 70% clamp. Liver enzyme (ALT) levels, inflammatory cytokine production and liver injury were quantified following 6 hr reperfusion.
Results: Both DAP12 and TREM2 were expressed at comparatively high levels by mouse and human liver DCs compared with blood or lymphoid tissue DCs. Mouse DCs lacking DAP12 or TREM2 exhibited increased levels of NFkB activation, co-stimulatory molecule expression, proinflammatory cytokine production and T cell stimulatory function. Silencing DAP12 expression in human liver DCs using siRNA also led to enhanced T cell stimulatory activity. Notably, unlike normal WT liver DCs, DAP12-/- liver DCs failed to inhibit T cell proliferative responses to aCD3/CD28 stimulation. In vivo, DAP12-/- mice subjected to liver IRI exhibited enhanced liver injury, accompanied by evidence of enhanced liver DC activation.
Conclusions: Our data reveal a close association between the expression of DAP12 and its triggering receptor TREM2 by murine and human liver DC. DAP12 negatively regulates liver DC function and promotes their ability to inhibit inflammatory responses. Absence of DAP12 augments liver IRI associated with enhanced liver DC activation.
CITATION INFORMATION: Nakao T., Ono Y., Dai H., Perez-Gutierrez A., Camirand G., Huang H., Geller D., Thomson A. DAP12 and Its Triggering Co-Receptor TREM2 Play Key Roles in Regulation of Mouse and Human Liver DC Function and Control of Liver Ischemia-Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Nakao T, Ono Y, Dai H, Perez-Gutierrez A, Camirand G, Huang H, Geller D, Thomson A. DAP12 and Its Triggering Co-Receptor TREM2 Play Key Roles in Regulation of Mouse and Human Liver DC Function and Control of Liver Ischemia-Reperfusion Injury [abstract]. https://atcmeetingabstracts.com/abstract/dap12-and-its-triggering-co-receptor-trem2-play-key-roles-in-regulation-of-mouse-and-human-liver-dc-function-and-control-of-liver-ischemia-reperfusion-injury/. Accessed June 2, 2025.« Back to 2018 American Transplant Congress