Pictured left to right: A. Thomson, D. Geller
Nakao T, Ono Y, Dai H, Nakano R, Perez-Gutierrez A, Camirand G, Huang H, Geller DA, Thomson AW. DAP12/TREM2 Expression by Mouse and Human Liver DC: Functional Implications and Regulation of Liver Ischemia-Reperfusion Injury. Hepatology. 2018 Oct 29. doi: 10.1002/hep.30334. [Epub ahead of print] PubMed PMID: 30372546.
ABSTRACT
Liver interstitial dendritic cells (DC) 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 DC remain unclear. We have shown recently that the transmembrane immunoadaptor DNAX-activating protein of 12 kDa (DAP12) negatively regulates mouse liver DC maturation and their pro-inflammatory 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 DC and other immune cells compared with DC in other tissues. We also examined the roles of DAP12 and TREM2 and their expression by liver DC in regulation of liver IRI. Injury was induced in DAP12-/- , TREM2-/- or WT mice by 1 hour of 70% clamping and quantified following 6 hours reperfusion. Both DAP12 and TREM2 were co-expressed at comparatively high levels by liver DC. Mouse liver DC lacking DAP12 or TREM2 displayed enhanced levels of nuclear factor κB and co-stimulatory molecule expression. Unlike normal WT liver DC, 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. Conclusions: 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 novel therapeutic target for control of acute liver injury/liver inflammatory disorders. This article is protected by copyright. All rights reserved.
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