Dumitriu Ingrid E, Bianchi Marco E, Bacci Monica, Manfredi Angelo A, Rovere-Querini Patrizia
Clinical Immunology Unit, H. San Raffaele Scientific Institute and Università Vita-Salute San Raffaele, via Olgettina 58, Milano 20132, Italy.
J Leukoc Biol. 2007 Jan;81(1):84-91. doi: 10.1189/jlb.0306171. Epub 2006 Oct 11.
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.
趋化因子调节由微生物成分许可的树突状细胞（DC）的迁移和成熟。我们最近发现，DC的功能，包括其激活幼稚、同种异体CD4 + T细胞的能力，需要核蛋白高迁移率族蛋白B1（HMGB1）的自分泌/旁分泌释放。我们在此表明，人髓样DC在成熟诱导后迅速分泌自身的HMGB1，重塑其基于肌动蛋白的细胞骨架，上调CCR7和CXCR4趋化因子受体，并获得响应趋化因子受体配体而迁移的能力。这些事件显然存在因果关系：在存在HMGB1特异性抗体的情况下用LPS刺激的DC无法上调CCR7和CXCR4受体的表达，也无法重排富含肌动蛋白的结构。此外，在抗HMGB1抗体存在下成熟的DC无法响应CCR7配体CCL19和CXCR4配体CXCL12而迁移。晚期糖基化终产物受体（RAGE）是HMGB1最具特征的膜受体，其阻断也会影响趋化因子受体的上调以及对CCL19和CXCL12的反应性。我们的数据表明，HMGB1的自分泌/旁分泌释放以及HMGB1/RAGE途径的完整性是DC迁移功能所必需的。
