DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis.
DAP12 (KARAP) is a transmembrane signaling adaptor for a family of innate immunoreceptors that have been shown to activate granulocytes and monocytes/macrophages, amplifying production of inflammatory cytokines. Contrasting with these data, recent studies suggest that DAP12 signaling has an inhibitory role in the macrophage response to microbial products (Hamerman, J.A., N.K. Tchao, C.A. Lowell, and L.L. Lanier. 2005. Nat. Immunol. 6:579-586). To determine the in vivo role for DAP12 signaling in inflammation, we measured the response of wild-type (WT) and DAP12-/- mice to septic shock. We show that DAP12-/- mice have improved survival from both endotoxemia and cecal ligation and puncture-induced septic shock. As compared with WT mice, DAP12-/- mice have decreased plasma cytokine levels and a decreased acute phase response during sepsis, but no defect in the recruitment of cells or bacterial control. In cells isolated after sepsis and stimulated ex vivo, DAP12 signaling augments lipopolysaccharide-mediated cytokine production. These data demonstrate that, during sepsis, DAP12 signaling augments the response to microbial products, amplifying inflammation and contributing to mortality.
Turnbull
Isaiah R
IR
Department of Pathology and Immunology, Department of Surgery, Washington University School of Medicine, St. Louis, MO 63110.
McDunn
Jonathan E
JE
Takai
Toshiyuki
T
Townsend
R Reid
RR
Cobb
J Perren
JP
Colonna
Marco
M
D000210:Acute-Phase Reaction / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016207:Cytokines / Q000378:metabolism; D019446:Endotoxemia / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D006098:Granulocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D010538:Peritonitis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D018805:Sepsis / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D015398:Signal Transduction / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D016207:Cytokines; C484963:Tyrobp protein, mouse