Submitted December 15, 2008
Accepted March 25, 2009
Activin A induces dendritic cell migration through the polarized release of CXCL12 and CXCL14
Laura Salogni, Tiziana Musso, Daniela Bosisio, Massimiliano Mirolo, Venkatakrishna R. Jala, Bodduluri Haribabu, Massimo Locati, and Silvano Sozzani*
Department of Biomedical Sciences and Biotechnology, Section of General Pathology and Immunology, University of Brescia, Brescia, Italy
Department of Public Health and Microbiology, University of Torino, Torino, Italy
Laboratory of Leukocyte Biology, Department of Translational Medicine, University of Milan, IRCCS Istituto Clinico Humanitas, Milan, Italy
James Graham Brown Cancer Center, University of Louisville, Louisville, KY, United States
* Corresponding author; email: sozzani{at}med.unibs.it.
Activin A is a dimeric protein, member of the TGF-
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 (iDC) through the activation of ALK4 and ActRIIA receptor chains. Conversely, Activin A was not active on plasmacytoid DC or mature myeloid DC. iDC migration to Activin A was PI3K
-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 iDC but not migration. These characteristics clearly differentiated the chemotactic activities of Activin A from TGF- and classic chemokines. By the use of combined pharmacological and low-density microarray analysis it was possible to define that Activin A-induced migration depends on the selective and polarized release of two chemokines, namely CXCL12 and CXCL14. This study extends the pro-inflammatory 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.
