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The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell-mediated resistance to metastasis.

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2019

Nat Immunol. 2019 Aug;20(8):1012-1022. doi: 10.1038/s41590-019-0417-y.

The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell-mediated resistance to metastasis.

I Mattiola;F Tomay;M De Pizzol;R Silva-Gomes;B Savino;T Gulic;A Doni;S Lonardi;M Astrid Boutet;A Nerviani;R Carriero;M Molgora;M Stravalaci;D Morone;IN Shalova;Y Lee;SK Biswas;G Mantovani;M Sironi;C Pitzalis;W Vermi;B Bottazzi;A Mantovani;M Locati

Humanitas Clinical and Research Center, Scientific Institute for Research and Healthcare, Rozzano, Italy. Laboratory of Innate Immunity, Department of Microbiology, Infectious Diseases and Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. Berlin Institute of Health, Berlin, Germany. Mucosal and Developmental Immunology, Deutsches Rheuma-Forschungszentrum, Berlin, Germany. Department of Medical Biotechnologies and Translational Medicine, University of Milan, Milan, Italy. Dompé Farmaceutici, Milan, Italy. Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Porto, Portugal. Medical Faculty, Department of Physiology and Immunology, University of Rijeka, Rijeka, Croatia. Department of Molecular and Translational Medicine, School of Medicine, University of Brescia, Brescia, Italy. Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK. Humanitas University, Pieve Emanuele, Italy. Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA. Faculty of Biomedical Sciences, Institute for Research in Biomedicine, Università della Svizzera italiana, Bellinzona, Switzerland. Singapore Immunology Network, Agency for Science, Technology & Research, Singapore, Singapore. Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Endocrinology Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy. Humanitas Clinical and Research Center, Scientific Institute for Research and Healthcare, Rozzano, Italy. Humanitas University, Pieve Emanuele, Italy.

Service type: Knockout mice

Abstract

The plasma membrane tetraspan molecule MS4A4A is selectively expressed by macrophage-lineage cells, but its function is unknown. Here we report that MS4A4A was restricted to murine and human mononuclear phagocytes and was induced during monocyte-to-macrophage differentiation in the presence of interleukin 4 or dexamethasone. Human MS4A4A was co-expressed with M2/M2-like molecules in subsets of normal tissue-resident macrophages, infiltrating macrophages from inflamed synovium and tumor-associated macrophages. MS4A4A interacted and colocalized with the β-glucan receptor dectin-1 in lipid rafts. In response to dectin-1 ligands, Ms4a4a-deficient macrophages showed defective signaling and defective production of effector molecules. In experimental models of tumor progression and metastasis, Ms4a4a deficiency in macrophages had no impact on primary tumor growth, but was essential for dectin-1-mediated activation of macrophages and natural killer (NK) cell-mediated metastasis control. Thus, MS4A4A is a tetraspan molecule selectively expressed in macrophages during differentiation and polarization, essential for dectin-1-dependent activation of NK cell-mediated resistance to metastasis.

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