Abstract
DAP12 is an ITAM-containing adapter that associates with receptors in myeloid and NK cells. DAP12-associated receptors can give activation signals leading to cytokine production; however, in some situations, DAP12 inhibits cytokine production stimulated through TLRs and FcRs. Here we show that Triggering Receptor Expressed on Myeloid cells (TREM)-2 is responsible for the DAP12-mediated inhibition in mouse macrophages. A chimeric receptor composed of the extracellular domain of TREM-2 and the cytoplasmic domain of DAP12 inhibited the TLR- and FcR-induced TNF production of DAP12-deficient macrophages, whereas a TREM-1 chimera did not. In wild-type macrophages, TREM-2 knockdown increased TLR-induced TNF production. A TREM-2 Fc fusion protein bound to macrophages, indicating that macrophages express a TREM-2 ligand. Thus, the interaction of TREM-2 and its ligand results in an inhibitory signal that can reduce the inflammatory response.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Adaptor Proteins, Signal Transducing / biosynthesis*
-
Adaptor Proteins, Signal Transducing / deficiency
-
Adaptor Proteins, Signal Transducing / genetics
-
Animals
-
Cells, Cultured
-
Inflammation Mediators / antagonists & inhibitors
-
Inflammation Mediators / metabolism
-
Ligands
-
Macrophages / immunology*
-
Macrophages / metabolism*
-
Membrane Glycoproteins / biosynthesis*
-
Membrane Glycoproteins / physiology
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Receptors, Fc / antagonists & inhibitors*
-
Receptors, Fc / biosynthesis
-
Receptors, Immunologic / biosynthesis*
-
Receptors, Immunologic / physiology
-
Toll-Like Receptors / antagonists & inhibitors*
-
Toll-Like Receptors / biosynthesis
-
Tumor Necrosis Factor-alpha / biosynthesis
Substances
-
Adaptor Proteins, Signal Transducing
-
Inflammation Mediators
-
Ligands
-
Membrane Glycoproteins
-
Receptors, Fc
-
Receptors, Immunologic
-
Toll-Like Receptors
-
Trem2 protein, mouse
-
Tumor Necrosis Factor-alpha
-
Tyrobp protein, mouse