The secretion of HMGB1 is required for the migration of maturing dendritic cells.
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.
Dumitriu
Ingrid E
IE
Clinical Immunology Unit, H. San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, via Olgettina 58, Milano 20132, Italy.
Bianchi
Marco E
ME
Bacci
Monica
M
Manfredi
Angelo A
AA
Rovere-Querini
Patrizia
P
D002478:Cells, Cultured; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D018925:Chemokines / Q000378:metabolism; D019742:Chemokines, CC / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D002633:Chemotaxis; D003599:Cytoskeleton / Q000378:metabolism; D003713:Dendritic Cells / Q000378:metabolism / Q000502:physiology*; D024243:HMGB1 Protein / Q000378:metabolism*; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D000067759:Receptor for Advanced Glycation End Products; D054400:Receptors, CCR7; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors*; D015854:Up-Regulation
C515460:CCL19 protein, human; C515370:CCR7 protein, human; C515255:CXCL12 protein, human; D054415:Chemokine CCL19; D054377:Chemokine CXCL12; D018925:Chemokines; D019742:Chemokines, CC; D019743:Chemokines, CXC; D024243:HMGB1 Protein; D000067759:Receptor for Advanced Glycation End Products; D054400:Receptors, CCR7; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D011971:Receptors, Immunologic