Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment -: An amplification cycle triggering cutaneous lupus erythematosus
Ultraviolet radiation-induced injury, chemokines, and leukocyte recruitment -: An amplification cycle triggering cutaneous lupus erythematosus
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DOI：
10.1002/art.21034
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发表时间：
2005-05-01
影响因子：
--
通讯作者：
Homey, B
中科院分区：
文献类型：
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作者：
Meller, S;Winterberg, F;Homey, B
客观的。探讨皮肤红斑狼疮（LE）发生和扩增过程中相关白细胞亚群的激活和招募途径。方法。采用实时定量聚合酶链反应对皮肤 LE 病变中所有已知的趋化因子及其受体进行全面分析，并利用免疫组织化学确定这些趋化因子和受体的细胞起源。此外，在体外和体内研究了细胞因子和紫外线 (UV) 光介导的相关趋化因子的激活途径。结果。在本研究中，我们确定了 CXCR3 配体 CXCL9（干扰素γ[IFN γ]诱导的单因子）、CXCL10（IFN γ 诱导蛋白 10）和 CXCL11（IFN 诱导的 T 细胞 α 趋化因子）是皮肤 LE 中表达最丰富的趋化因子家族成员。这些配体的表达与主要由表达 CXCR3 的细胞组成的明显炎症浸润相对应，包括皮肤归巢淋巴细胞和血液树突细胞抗原 2 阳性浆细胞样树突细胞 (PDC)。在皮肤 LE 病变内，PDC 在真皮内积聚并被激活产生 I 型 IFN，如通过 IFN α 诱导基因 IRF7 和 MxA 的表达检测到的。反过来，IFN α 是皮肤细胞成分中 CXCR3 配体的有效且快速的诱导剂。此外，我们证明炎症 CXCR3 配体在招募致病相关白细胞亚群期间与稳态趋化因子 CXCL12（基质细胞衍生因子 1）协同作用。此外，我们发现 UVB 照射诱导 CCL27（皮肤 T 细胞吸引趋化因子）从表皮区室释放到真皮区室，并上调角质形成细胞中一组不同趋化因子的表达。结论。综上所述，我们的数据表明了一个放大周期，其中紫外线诱导的损伤诱导细胞凋亡、坏死和趋化因子的产生。这些机制反过来介导自身免疫 T 细胞和产生 IFN α 的 PDC 的招募和激活，随后释放更多的效应细胞因子，从而放大趋化因子的产生和白细胞的招募，最终导致皮肤 LE 表型的发展。
Objective. To investigate the activation and recruitment pathways of relevant leukocyte subsets during the initiation and amplification of cutaneous lupus erythematosus (LE).Methods. Quantitative real-time polymerase chain reaction was used to perform a comprehensive analysis of all known chemokines and their receptors in cutaneous LE lesions, and the cellular origin of these chemokines and receptors was determined using immunohistochemistry. Furthermore, cytokine- and ultraviolet (UV) light-mediated activation pathways of relevant chemokines were investigated in vitro and in vivo.Results. In the present study, we identified the CXCR3 ligands CXCL9 (interferon-gamma [IFN gamma]-induced monokine), CXCL10 (IFN gamma-inducible protein 10), and CXCL11 (IFN-inducible T cell alpha chemoattractant) as being the most abundantly expressed chemokine family members in cutaneous LE. Expression of these ligands corresponded with the presence of a marked inflammatory infiltrate consisting of mainly CXCR3-expressing cells, including skin-homing lymphocytes and blood dendritic cell antigen 2-positive plasmacytoid dendritic cells (PDCs). Within cutaneous LE lesions, PDCs accumulated within the dermis and were activated to produce type I IFN, as detected by the expression of the IFN alpha-inducible genes IRF7 and MxA. IFN alpha, in turn, was a potent and rapid inducer of CXCR3 ligands in cellular constituents of the skin. Furthermore, we demonstrated that the inflammatory CXCR3 ligands cooperate with the homeostatic chemokine CXCL12 (stromal cell-derived factor 1) during the recruitment of pathogenically relevant leukocyte subsets. Moreover, we showed that UVB irradiation induces the release of CCL27 (cutaneous T cell-attracting chemokine) from epidermal compartments into dermal compartments and up-regulates the expression of a distinct set of chemokines in keratinocytes.Conclusion. Taken together, our data suggest an amplification cycle in which UV light-induced injury induces apoptosis, necrosis, and chemokine production. These mechanisms, in turn, mediate the recruitment and activation of autoimmune T cells and IFN alpha-producing PDCs, which subsequently release more effector cytokines, thus amplifying chemokine production and leukocyte recruitment, finally leading to the development of a cutaneous LE phenotype.