Survival and migration of human dendritic cells are regulated by an IFN-α-inducible Axl/Gas6 pathway

Sara Scutera, Tiziana Fraone, Tiziana Musso, Paola Cappello, Silvia Rossi, Daniele Pierobon, Zane Orinska, Ralf Paus, Silvia Bulfone-Paus, Mirella Giovarelli

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45 Scopus citations

Abstract

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-α 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-α. 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-α-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-α.

Original languageEnglish (US)
Pages (from-to)3004-3013
Number of pages10
JournalJournal of Immunology
Volume183
Issue number5
DOIs
StatePublished - Sep 1 2009

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Scutera, S., Fraone, T., Musso, T., Cappello, P., Rossi, S., Pierobon, D., Orinska, Z., Paus, R., Bulfone-Paus, S., & Giovarelli, M. (2009). Survival and migration of human dendritic cells are regulated by an IFN-α-inducible Axl/Gas6 pathway. Journal of Immunology, 183(5), 3004-3013. https://doi.org/10.4049/jimmunol.0804384