DNAX Activating Protein of 12 kDa/Triggering Receptor Expressed on Myeloid Cells 2 Expression by Mouse and Human Liver Dendritic Cells: Functional Implications and Regulation of Liver Ischemia–Reperfusion Injury

Abstract

Liver interstitial dendritic cells (DCs) have been implicated in the control of ischemia–reperfusion injury (IRI) and host immune responses following liver transplantation. Mechanisms underlying these regulatory functions of hepatic DCs remain unclear. We have shown recently that the transmembrane immunoadaptor DNAX‐activating protein of 12 kDa (DAP12) negatively regulates mouse liver DC maturation and proinflammatory and immune stimulatory functions. Here, we used PCR analysis and flow cytometry to characterize expression of DAP12 and its associated triggering receptor, triggering receptor expressed on myeloid cells 2 (TREM2), by mouse and human liver DCs and other immune cells compared with DCs in other tissues. We also examined the roles of DAP12 and TREM2 and their expression by liver DCs in the regulation of liver IRI. Injury was induced in DAP12–/–, TREM2–/–, or wild‐type (WT) mice by 1 hour of 70% clamping and quantified following 6 hours of reperfusion. Both DAP12 and TREM2 were coexpressed at comparatively high levels by liver DCs. Mouse liver DCs lacking DAP12 or TREM2 displayed enhanced levels of nuclear factor κB and costimulatory molecule expression. Unlike normal WT liver DCs, DAP12–/– liver DC failed to inhibit proliferative responses of activated T cells. In vivo, DAP12–/– and TREM2–/– mice exhibited enhanced IRI accompanied by augmented liver DC activation. Elevated alanine aminotransferase levels and tissue injury were markedly reduced by infusion of WT but not DAP12–/– DC. Conclusion: Our data reveal a close association between DAP12 and TREM2 expression by liver DC and suggest that, by negatively regulating liver DC stimulatory function, DAP12 promotes their control of hepatic inflammatory responses; the DAP12/TREM2 signaling complex may represent a therapeutic target for control of acute liver injury/liver inflammatory disorders.

Protective and therapeutic effects of nanoliposomal quercetin on acute liver injury in rats

“…Many kinds of factors including biological damage such as with hepatitis virus [17], chemical damage such as with drugs [18,19], and physical damage such as with liver transplantationcan [20,21] lead to liver injury. The use of carbon tetrachloride [22] and other composite factors such as a high-fat, high-cholesterol, and low-protein diet as well as alcohol drinking can induce liver injury models in animals, with pathological results very similar to human chronic liver diseases.…”

Vagus Nerve Stimulation Attenuates Hepatic Ischemia/Reperfusion Injury via the Nrf2/HO-1 Pathway

“…Among a considerable variety of underlying mechanisms in hepatic I/R injury, increased inflammatory reactions play a pivotal part [5, 23]. The VNS-mediated cholinergic anti-inflammatory pathway has been well studied in the liver.…”

Transplant Tolerance Induction: Insights From the Liver

“…Graft-infiltrating CD-DC expressed PDL1 and IL-10 that subvert anti-donor T cell responses and promote death of graft-infiltrating CD8 + T cells to promote liver graft tolerance (106). The transmembrane immuno-adaptor DNAX-activating protein of 12 kDa (DAP12) has been shown to negatively regulate conventional liver myeloid DC maturation, migration to host lymphoid tissue, and T cell allo-stimulatory capability (107,108). DAP12 −/− liver grafts exhibit low levels of Tregs and fail to induce liver transplant tolerance (107).…”