TY - JOUR
T1 - The macrophage tetraspan MS4A4A enhances dectin-1-dependent NK cell–mediated resistance to metastasis
AU - Mattiola, Irene
AU - Tomay, Federica
AU - De Pizzol, Maria
AU - Silva-Gomes, Rita
AU - Savino, Benedetta
AU - Gulic, Tamara
AU - Doni, Andrea
AU - Lonardi, Silvia
AU - Astrid Boutet, Marie
AU - Nerviani, Alessandra
AU - Carriero, Roberta
AU - Molgora, Martina
AU - Stravalaci, Matteo
AU - Morone, Diego
AU - Shalova, Irina N.
AU - Lee, Yunquin
AU - Biswas, Subhra K.
AU - Mantovani, Giovanna
AU - Sironi, Marina
AU - Pitzalis, Costantino
AU - Vermi, William
AU - Bottazzi, Barbara
AU - Mantovani, Alberto
AU - Locati, Massimo
N1 - Funding Information:
A.M. is a recipient of commercial research grants from Novartis; a consultant/advisory board member for Novartis, Roche, Ventana, Pierre Fabre, Verily, AbbVie, Compugen, Macrophage Therapeutics, AstraZeneca, Biovelocita, BG Fund, Third Rock and Verseau; an inventor of patents related to PTX3 and other innate immunity molecules; and also receives royalties for reagents related to innate immunity.
Funding Information:
The authors thank C. Garlanda and M. Kallikourdis (Humanitas Clinical and Research Center, Scientific Institute for Research and Healthcare (IRCCS)) for providing cDNAs of murine leukocyte subsets, and T. Irimura (Juntendo University School of Medicine, Tokyo, Japan) and R. Giavazzi (Mario Negri Institute, Milan, Italy) for providing MC38 and SL4 cells. Technical assistance from A. Fontanini, C. Perrucchini, T. Schorn, R. Porte and F. Pasqualini is acknowledged. A. Inforzato (Humanitas Clinical and Research Center, IRCCS), A. Diefenbach (Charité – Universitätsmedizin Berlin, Germany) and L. Florin (University Medical Centre of the Johannes Gutenberg University, Mainz, Germany) are gratefully acknowledged for their support and discussion. Financial support came from Fondazione Cariplo (grant no. 2015–0564 to A.M.), Cluster Alisei (grant no. MEDINTECH CTN01_00177_962865 to A.M.), the European Research Council (grant no. 669415-PHII to A.M.), the Italian Association for Cancer Research (AIRC IG-2016 grant no. 19014 to A.M.; AIRC 5×1000 grant no. 21147 to A.M.; AIRC IG-2016 grant no. 19213 to M.L.), Medical Research Council (Pathobiology of Early Arthritis Cohort grant no. 36661 to C.P.) and Arthritis Research UK Experimental Treatment Centre (grant no. 20022 to C.P.). I.M. was supported by a Mario and Valeria Rindi fellowship and a Fellowship for abroad from the Italian Foundation for Cancer Research, and by a European Federation of Immunological Societies-IL short-term fellowship. B.S. was supported by Ministero della Salute (progetto Finalizzata GR-2013-02356522). R.S.G. was supported by a PhD studentship (PD/BD/114138/2016) from Fundação para a Ciência e Tecnologia, Portugal. S.K.B. was supported by core funding from Singapore Immunology Network—Agency for Science, Technology & Research (A*STAR), Singapore. F.T. was supported by a fellowship from the A*STAR Research Attachment Program, Singapore. S.L. was supported by Fondazione Beretta, Italy.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85068563633&partnerID=8YFLogxK
U2 - 10.1038/s41590-019-0417-y
DO - 10.1038/s41590-019-0417-y
M3 - Article
C2 - 31263276
AN - SCOPUS:85068563633
SN - 1529-2908
VL - 20
SP - 1012
EP - 1022
JO - Nature immunology
JF - Nature immunology
IS - 8
ER -