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Sci. Signal., 28 October 2008
Vol. 1, Issue 43, p. ra11
[DOI: 10.1126/scisignal.1159665]


Essential Role of DAP12 Signaling in Macrophage Programming into a Fusion-Competent State

Laura Helming1*, Elena Tomasello2,3,4, Themis R. Kyriakides5,6,7, Fernando O. Martinez1, Toshiyuki Takai8,9, Siamon Gordon1{dagger}{ddagger}, and Eric Vivier2,3,4,10{dagger}{ddagger}

1 Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford OX1 3RE, UK.
2 Centre d’Immunologie de Marseille-Luminy, Université de la Méditerranée, case 906, Campus de Luminy, 13288 Marseille, France.
3 INSERM, U631, case 906, Campus de Luminy, 13288 Marseille, France.
4 CNRS, UMR6102, case 906, Campus de Luminy, 13288 Marseille, France.
5 Vascular Biology and Therapeutics Program, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
6 Department of Pathology, Yale University School of Medicine, New Haven, CT 06520, USA.
7 Department of Biomedical Engineering, Yale University School of Medicine, New Haven, CT 06520, USA.
8 Department of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, Seiryo 4-1, Aoba-ku, Sendai 980-8575, Japan.
9 Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology Corporation (JST), Honcho 4-1-8, Kawaguchi, Saitama 332-0012, Japan.
10 Assistance Publique-Hôpitaux de Marseille, Hôpital de la Conception, 13385 Marseille, France.

* Present address: Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Trogerstrasse 30, 81675 Munich, Germany.

{ddagger} Joint senior authors.

Abstract: Multinucleated giant cells, formed by fusion of macrophages, are a hallmark of granulomatous inflammation. With a genetic approach, we show that signaling through the adaptor protein DAP12 (DNAX activating protein of 12 kD), its associated receptor triggering receptor expressed by myeloid cells 2 (TREM-2), and the downstream protein tyrosine kinase Syk is required for the cytokine-induced formation of giant cells and that overexpression of DAP12 potentiates macrophage fusion. We also present evidence that DAP12 is a general macrophage fusion regulator and is involved in modulating the expression of several macrophage-associated genes, including those encoding known mediators of macrophage fusion, such as DC-STAMP and Cadherin 1. Thus, DAP12 is involved in programming of macrophages through the regulation of gene and protein expression to induce a fusion-competent state.

{dagger} To whom correspondence should be addressed. E-mail: siamon.gordon{at} (S.G.) and vivier{at} (E.V.)

Citation: L. Helming, E. Tomasello, T. R. Kyriakides, F. O. Martinez, T. Takai, S. Gordon, E. Vivier, Essential Role of DAP12 Signaling in Macrophage Programming into a Fusion-Competent State. Sci. Signal. 1, ra11 (2008).

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