Cutting edge: inhibition of TLR and FcR responses in macrophages by triggering receptor expressed on myeloid cells (TREM)-2 and DAP12.
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.
Hamerman
Jessica A
JA
Department of Microbiology and Immunology, University of California-San Francisco, 514 Parnassus Avenue, San Francisco, CA 94143, USA.
Jarjoura
Jessica R
JR
Humphrey
Mary Beth
MB
Nakamura
Mary C
MC
Seaman
William E
WE
Lanier
Lewis L
LL
D048868:Adaptor Proteins, Signal Transducing / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011961:Receptors, Fc / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D011971:Receptors, Immunologic / Q000096:biosynthesis* / Q000502:physiology; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D018836:Inflammation Mediators; D008024:Ligands; D008562:Membrane Glycoproteins; D011961:Receptors, Fc; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; C498716:Trem2 protein, mouse; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse