Blood Journal
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Activin A induces dendritic cell migration through the polarized release of CXC chemokine ligands 12 and 14

  1. Laura Salogni1,
  2. Tiziana Musso2,
  3. Daniela Bosisio1,
  4. Massimiliano Mirolo3,
  5. Venkatakrishna R. Jala4,
  6. Bodduluri Haribabu4,
  7. Massimo Locati3, and
  8. Silvano Sozzani1
  1. 1Department of Biomedical Sciences and Biotechnology, Section of General Pathology and Immunology, University of Brescia, Brescia, Italy;
  2. 2Department of Public Health and Microbiology, University of Torino, Torino, Italy;
  3. 3Laboratory of Leukocyte Biology, Department of Translational Medicine, University of Milan, Istituto Clinico Humanitas, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Rozzano, Italy; and
  4. 4James Graham Brown Cancer Center, University of Louisville, KY

Abstract

Activin A is a dimeric protein, member of the transforming growth factor (TGF)–β family that plays a crucial role in wound repair and in fetal tolerance. Emerging evidence also proposes activin A as a key mediator in inflammation. This study reports that activin A induces the directional migration of immature myeloid dendritic cells (iDCs) through the activation of ALK4 and ActRIIA receptor chains. Conversely, activin A was not active on plasmacytoid dendritic cells (DCs) or mature myeloid DCs. iDC migration to activin A was phosphatidylinositol 3-kinase γ–dependent, Bordetella pertussis toxin– and cycloheximide-sensitive, and was inhibited by M3, a viral-encoded chemokine-binding protein. In a real-time video microscopy-based migration assay, activin A induced polarization of iDCs, but not migration. These characteristics clearly differentiated the chemotactic activities of activin A from TGF-β and classic chemokines. By the use of combined pharmacologic and low-density microarray analysis, it was possible to define that activin-A–induced migration depends on the selective and polarized release of 2 chemokines, namely CXC chemokine ligands 12 and 14. This study extends the proinflammatory role of activin A to DC recruitment and provides a cautionary message about the reliability of the in vitro chemotaxis assays in discriminating direct versus indirect chemotactic agonists.

  • Submitted December 14, 2008.
  • Accepted March 25, 2009.
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