Hu Yang, Ivashkiv Lionel B
Graduate Program in Neuroscience, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
J Immunol. 2006 May 15;176(10):6022-33. doi: 10.4049/jimmunol.176.10.6022.
Type I IFNs induce differentiation of dendritic cells (DCs) with potent Ag-presenting capacity, termed IFN-alpha DCs, that have been implicated in the pathogenesis of systemic lupus erythematosus. In this study, we found that IFN-alpha DCs exhibit enhanced migration across the extracellular matrix (ECM) in response to chemokines CCL3 and CCL5 that recruit DCs to inflammatory sites, but not the lymphoid-homing chemokine CCL21. IFN-alpha DCs expressed elevated matrix metalloproteinase-9 (MMP-9), which mediated increased migration across ECM. Unexpectedly, MMP-9 and its cell surface receptors CD11b and CD44 were required for enhanced CCL5-induced chemotaxis even in the absence of a matrix barrier. MMP-9, CD11b, and CD44 selectively modulated CCL5-dependent activation of JNK that was required for enhanced chemotactic responses. These results establish the migratory phenotype of IFN-alpha DCs and identify an important role for costimulation of chemotactic responses by synergistic activation of JNK. Thus, cell motility is regulated by integrating signaling inputs from chemokine receptors and molecules such as MMP-9, CD11b, and CD44 that also mediate cell interactions with inflammatory factors and ECM.
I型干扰素可诱导具有强大抗原呈递能力的树突状细胞（DCs）分化，即所谓的干扰素α DCs，其与系统性红斑狼疮的发病机制有关。在本研究中，我们发现干扰素α DCs在趋化因子CCL3和CCL5的作用下，跨细胞外基质（ECM）的迁移能力增强，这些趋化因子将DCs募集到炎症部位，但淋巴归巢趋化因子CCL21则无此作用。干扰素α DCs表达升高的基质金属蛋白酶-9（MMP-9），其介导了跨ECM迁移的增加。出乎意料的是，即使在没有基质屏障的情况下，MMP-9及其细胞表面受体CD11b和CD44对于增强CCL5诱导的趋化作用也是必需的。MMP-9、CD11b和CD44选择性地调节了增强趋化反应所需的CCL5依赖性JNK激活。这些结果确立了干扰素α DCs的迁移表型，并确定了通过JNK协同激活对趋化反应进行共刺激的重要作用。因此，细胞运动性是通过整合来自趋化因子受体以及诸如MMP-9、CD11b和CD44等分子的信号输入来调节的，这些分子也介导细胞与炎症因子和ECM的相互作用。
