Enhanced Toll-like receptor responses in the absence of signaling adaptor DAP12.
DAP12 is a signaling adaptor containing an immunoreceptor tyrosine-based activation motif (ITAM) that pairs with receptors on myeloid cells and natural killer cells. We examine here the responses of mice lacking DAP12 to stimulation through Toll-like receptors (TLRs). Unexpectedly, DAP12-deficient macrophages produced higher concentrations of inflammatory cytokines in response to a variety of pathogenic stimuli. Additionally, macrophages deficient in spleen tyrosine kinase (Syk), which signals downstream of DAP12, showed a phenotype identical to that of DAP12-deficient macrophages. DAP12-deficient mice were more susceptible to endotoxic shock and had enhanced resistance to infection by the intracellular bacterium Listeria monocytogenes. These data suggest that one or more DAP12-pairing receptors negatively regulate signaling through TLRs.
Hamerman
Jessica A
JA
Department of Microbiology and Immunology and the Cancer Research Institute, University of California San Francisco, San Francisco, California 94143, USA.
Tchao
Nadia K
NK
Lowell
Clifford A
CA
Lanier
Lewis L
LL
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D004792:Enzyme Precursors / Q000172:deficiency / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D007113:Immunity, Innate; D047908:Intracellular Signaling Peptides and Proteins; D008089:Listeria monocytogenes / Q000276:immunology / Q000472:pathogenicity; D008264:Macrophages / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012772:Shock, Septic / Q000209:etiology; D015398:Signal Transduction; D000072377:Syk Kinase; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D048868:Adaptor Proteins, Signal Transducing; D000893:Anti-Inflammatory Agents; D016207:Cytokines; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C484963:Tyrobp protein, mouse; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D048049:Extracellular Signal-Regulated MAP Kinases