Inhibition of Toll-like receptor and Fc receptor responses in macrophages by TREM-2 and DAP12 (44.7)

Abstract

Abstract DAP12 is a transmembrane signaling adapter that contains an immunoreceptor tyrosine-based activation motif (ITAM) in its cytoplasmic domain and is expressed in myeloid cells and natural killer cells. DAP12 associates with receptors that do not have intrinsic signaling ability and therefore use DAP12 to propagate signals. We examined the inflammatory response in macrophages lacking DAP12. Surprisingly, DAP12-deficient macrophages produced increased amounts of inflammatory cytokines in response to Toll-like receptor and Fc receptor stimulation, demonstrating that DAP12 inhibits inflammatory responses in wild-type macrophages. This inhibition was dependent upon the DAP12 ITAM. In vivo, DAP12-deficient mice were more susceptible to LPS/D-galactosamine-induced shock and more resistant to Listeria monocytogenes infection. TREM-2, a DAP12-associated Ig superfamily receptor, was responsible for the DAP12-mediated inhibition of TLR and FcR responses in macrophages. Additionally, a fusion protein containing the extracellular domain of TREM-2 bound to macrophages. These results suggest that the interaction of TREM-2 and its ligand on macrophages results in an inhibitory signal that can reduce the macrophage inflammatory response.