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

Laura Helming^1*, Elena Tomasello^2,3,4, Themis R. Kyriakides^5,6,7, Fernando O. Martinez¹, Toshiyuki Takai^8,9, Siamon Gordon¹, and Eric Vivier^2,3,4,10

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.

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.

To whom correspondence should be addressed. E-mail: siamon.gordon{at}path.ox.ac.uk (S.G.) and vivier{at}ciml.univ-mrs.fr (E.V.)

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