Unmasking the mechanism of formation of multinucleated giant cells

November 25 2008

A research team in Marseilles-Luminy Immunology Centre (Inserm-CNRS-Université de la Méditerranée) directed by Eric Vivier, in collaboration with a laboratory in Oxford, has just shown that a membrane protein called DAP12 is necessary and sufficient for the formation of the multinucleated giant cells involved in inflammation in patients with tuberculosis, sarcoidosis and schistosomiasis as well as other diseases. These cells also cause the gradual degradation of biomaterial implants. The researchers showed that DAP12 present on macrophages triggers a cascade of signals leading to the synthesis of the proteins involved in fusion. If this cascade is inhibited, giant cell formation may be reduced, and biomaterials preserved. The results are published in Science Signaling, the most recent offshoot of the review Science.

Multinucleated giant cells are formed by the fusion of macrophages at inflammation sites in certain infectious or non-infectious disease in patients with tuberculosis, sarcoidosis (inflammation of the lungs), schistosomiasis (a parasite infection) or at biomaterial implantation sites. Biomaterials are implanted to repair injured tissues or strengthen the function of defective organs in the form of prostheses, implants, lenses or surgical materials.

Macrophages eliminate cell debris and pathogenic agents and are therefore legitimately present at the sites of infection or inflammation. However the reason for their fusion into giant cells has remained a mystery since their discovery in 1868. They are thought to cause lesions in the case of tuberculosis and may play a key role in the onset of sarcoidosis, a chronic inflammation of the lung. Moreover, clinicians know that these cells have a harmful effect on implants by damaging biomaterials. Hence the importance of improving our understanding of the mechanisms and signals leading to the formation of these cells with the final goal of modulating their activity.

The team of Eric Vivier, director of the Marseilles-Luminy Immunology Centre, Inserm unit 631, in collaboration with a laboratory at Oxford, has just thrown light on these mechanisms. Previous studies had shown that large amounts of a transmembrane protein DAP12 (also called KARAP) were present in immune cells, including macrophages, and that this was involved in the formation of osteoclasts, bone cells also obtained by macrophage fusion. The scientists therefore decided to investigate this molecule.

They inactivated the gene coding for this protein in mice with an implant. The results were conclusive: in these rodents, there were almost no giant cells around the implant despite a similar number of macrophages in control mice. On the contrary, over-expression of the DAP12 protein caused the formation of large numbers of giant cells in vitro and in vivo. The scientists extended these studies by “dissecting” the DAP12-dependant signalling pathway. They noted that this protein binds to a macrophage membrane receptor (TREM2), causing the activation of a tyrosine kinase protein Syk. This cascade of events modifies the control of many genes coding for the proteins involved in cell fusion such as transmembrane receptors or adhesion proteins. It stimulates the expression of almost five hundred genes and inhibits the expression of approximately seven hundred others.

These studies therefore made it possible to show that the protein DAP12 and the cascade of signals that it causes, are essential for the formation of giant cells.

This succession of events in the cell “prepares” macrophages for fusion by controlling the numerous genes coding for fusion proteins.

The protein DAP12, by recognising the TREM2 receptor present on the macrophage membrane, activates the formation of multinucleated giant macrophages.

“The proteins involved in this cascade of signals, in particular TREM2 and syk provide interesting new therapeutic targets for the treatment of patients with sarcoidosis or preservation of the integrity of implants, explained Eric Vivier. The inhibition of the protein syk is already studied in other indications and may therefore be all the more promising”.

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"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. Martinez,1Toshiyuki Takai,8,9 Siamon Gordon,1 Eric Vivier2,3,4,10

(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) Unité Inserm 631, 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.

Science Signaling Volume 1 Issue 43 ra11, DOI: 10.1126/scisignal.1159665

Researcher’s contact details

Eric Vivier
Tel.: 04 91 26 94 13

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