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-Inducible Axl/Gas6 Pathway1
,¶
* Department of Public Health and Microbiology,
Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, and Department of Medicine and Experimental Oncology, University of Torino, Torino, Italy;
Department of Immunology and Cell Biology, Research Center Borstel, Borstel, Germany;
Department of Dermatology, University of Lübeck, Lübeck, Germany; and
¶ School of Translational Medicine, University of Manchester, Manchester, United Kingdom
Axl, a prototypic member of the transmembrane tyrosine kinase receptor family, is known to regulate innate immunity. In this study, we show that Axl expression is induced by IFN-
during human dendritic cell (DC) differentiation from monocytes (IFN/DC) and that constitutively Axl-negative, IL-4-differentiated DC (IL-4/DC) can be induced to up-regulate Axl by IFN-. This effect is inhibited by TLR-dependent maturation stimuli such as LPS, poly(I:C), TLR7/8 ligand, and CD40L. LPS-induced Axl down-regulation on the surface of human IFN--treated DC correlates with an increased proteolytic cleavage of Axl and with elevated levels of its soluble form. GM6001 and TAPI-1, general inhibitors of MMP and ADAM family proteases, restored Axl expression on the DC surface and diminished Axl shedding. Furthermore, stimulation of Axl by its ligand, Gas6, induced chemotaxis of human DC and rescued them from growth factor deprivation-induced apoptosis. Our study provides the first evidence that Gas6/Axl-mediated signaling regulates human DC activities, and identifies Gas6/Axl as a new DC chemotaxis pathway. This encourages one to explore whether dysregulation of this novel pathway in human DC biology is involved in autoimmunity characterized by high levels of IFN-.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by Ministero dell’Istruzione Università e Ricerca, Programma di Ricerca Scientifica di Interesse Nazionale, and Regione Piemonte-Progetti di Ricerca Sanitaria Finalizzata e Applicata, and by grants from the Fondazione Casse di Risparmio di Torino (Progetto Alfieri) and Deutsche Forschungsgemeinschaft (to S.B.-P.). P.C. is a recipient of Fondazione Italiana per la Ricerca Sul Cancro, fellowship; T.F. is a recipient of Fondazione Angela Bossolasco fellowship.
S.S. and T.F. performed research, analyzed and interpreted data, and wrote the paper; T.M. designed research, and analyzed and interpreted data; P.C. and Z.O. analyzed and interpreted data; D.P. and S.R. performed research and collected data; R.P. interpreted data and wrote the paper; and S.B.-P. and M.G. designed research, analyzed and interpreted data, and wrote the paper.
2 S.S., T.F., S.B.-P., and M.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Silvia Bulfone-Paus, Department of Immunology and Cell Biology, Research Center Borstel, Parkallee 22, D-23845 Borstel, Germany. E-mail address: sbulfone{at}fz-borstel.de
4 Abbreviations used in this paper: TAM, Tyro3, Axl, and Mer; BMDC, bone marrow-derived dendritic cell; DC, dendritic cell; HPRT, hypoxanthine phosphoribosyltransferase; MFI, mean fluorescence intensity; pAb, polyclonal Ab; PI, propidium iodide; sAxl, soluble Axl; SOCS, suppressor of cytokine signaling; TACE, TNF- converting enzyme; ADAM, a disintegrin and metalloproteinase; MMP, matrix metalloproteinase.
5 The online version of this article contains supplemental material.
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