Journal of Leukocyte Biology
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Originally published online as doi:10.1189/jlb.0306171 on October 11, 2006

Published online before print October 11, 2006
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(Journal of Leukocyte Biology. 2007;81:84-91.)
© 2007 by Society for Leukocyte Biology

The secretion of HMGB1 is required for the migration of maturing dendritic cells

Ingrid E. Dumitriu*, Marco E. Bianchi{dagger}, Monica Bacci*, Angelo A. Manfredi* and Patrizia Rovere-Querini*,1

* Clinical Immunology Unit and
{dagger} Chromatin Dynamics Unit, H San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, Milan, Italy

1Correspondence: Cancer Immunotherapy and Gene Therapy Program, Clinical Immunology Unit, H. San Raffaele Scientific Institute, via Olgettina 58, Milano 20132, Italy. E-mail: rovere.patrizia{at}hsr.it

ABSTRACT

Chemokines regulate the migration and the maturation of dendritic cells (DC) licensed by microbial constituents. We have recently found that the function of DC, including their ability to activate naïve, allogeneic CD4+ T cells, requires the autocrine/paracrine release of the nuclear protein high mobility group box 1 (HMGB1). We show here that human myeloid DC, which rapidly secrete upon maturation induction their own HMGB1, remodel their actin-based cytoskeleton, up-regulate the CCR7 and the CXCR4 chemokine receptors, and acquire the ability to migrate in response to chemokine receptor ligands. The events are apparently causally related: DC challenged with LPS in the presence of HMGB1-specific antibodies fail to up-regulate the expression of the CCR7 and CXCR4 receptors and to rearrange actin-rich structures. Moreover, DC matured in the presence of anti-HMGB1 antibodies fail to migrate in response to the CCR7 ligand CCL19 and to the CXCR4 ligand CXCL12. The blockade of receptor for advanced glycation end products (RAGE), the best-characterized membrane receptor for HMGB1, impinges as well on the up-regulation of chemokine receptors and on responsiveness to CCL19 and CXCL12. Our data suggest that the autocrine/paracrine release of HMGB1 and the integrity of the HMGB1/RAGE pathway are required for the migratory function of DC.

Key Words: cell trafficking • cell death




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