Cutting Edge: TREM-2 Attenuates Macrophage Activation

TLDR

TREM‑2 signals through DAP12 to regulate myeloid cell function, but its in vivo expression and role in immunity have been unclear. The authors aim to show that TREM‑2 is expressed on macrophages and that it restrains cytokine production upon TLR stimulation. They find that TREM‑2 is expressed on newly differentiated and alternatively activated macrophages, is suppressed by LPS/IFN‑γ, and that TREM‑2−/‑ mice exhibit heightened cytokine responses to TLR ligands, fully explaining the hyper‑cytokine phenotype of DAP12−/‑ macrophages.

Abstract

Abstract The triggering receptor expressed on myeloid cells 2 (TREM-2) delivers intracellular signals through the adaptor DAP12 to regulate myeloid cell function both within and outside the immune system. The role of TREM-2 in immunity has been obscured by the failure to detect expression of the TREM-2 protein in vivo. In this study, we show that TREM-2 is expressed on macrophages infiltrating the tissues from the circulation and that alternative activation with IL-4 can induce TREM-2. TREM-2 expression is abrogated by macrophage maturation with LPS of IFN-γ. Using TREM-2−/− mice, we find that TREM-2 functions to inhibit cytokine production by macrophages in response to the TLR ligands LPS, zymosan, and CpG. Furthermore, we find that TREM-2 completely accounts for the increased cytokine production previously reported by DAP12−/− macrophages. Taken together, these data show that TREM-2 is expressed on newly differentiated and alternatively activated macrophages and functions to restrain macrophage activation.