The Journal of Experimental Medicine
Avanti Polar Lipids
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Published 1 August 2005. doi:10.1084/jem.20050986
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 202, Number 3, 363-369
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BRIEF DEFINITIVE REPORT

 DAP12 (KARAP) amplifies inflammation and increases mortality from endotoxemia and septic peritonitis

Isaiah R. Turnbull1, Jonathan E. McDunn2, Toshiyuki Takai4,5, R. Reid Townsend3, J. Perren Cobb2, and Marco Colonna1

1 Department of Pathology and Immunology, Department of Surgery
2 Cellular Injury and Adaptation Laboratory, Department of Surgery
3 Department of Medicine and Proteomics Center, Washington University School of Medicine, St. Louis, MO 63110
4 Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Aoba-ku, Sendai 980-8575, Japan
5 Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan

CORRESPONDENCE Marco Colonna: mcolonna{at}pathology.wustl.edu

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.


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