TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus.
TWEAK/Fn14 Activation Participates in Ro52-Mediated Photosensitization in Cutaneous Lupus Erythematosus.
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DOI：
10.3389/fimmu.2017.00651
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发表时间：
2017
影响因子：
7.3
通讯作者：
Xia Y
中科院分区：
文献类型：
--
作者：
Liu Y;Xu M;Min X;Wu K;Zhang T;Li K;Xiao S;Xia Y
肿瘤坏死因子 (TNF) 样弱凋亡诱导剂 (TWEAK) 与其唯一受体成纤维细胞生长因子诱导型 14 (Fn14) 结合，参与各种炎症反应。最近，发现 TWEAK/Fn14 激活在皮肤红斑狼疮 (CLE) 病变中显着。本研究旨在进一步揭示该通路在 Ro52 介导的光敏化中的潜在作用。在 CLE 患者的皮损中测定了 TWEAK、Fn14 和 Ro52。小鼠角质形成细胞接受紫外线 B (UVB) 照射或 TWEAK 刺激，并检测 Ro52 和促炎细胞因子。通过 TWEAK 刺激共培养的角质形成细胞来评估 J774.2 巨噬细胞的趋化性。我们发现 TWEAK、Fn14 和下游细胞因子在 Ro52 过表达的 CLE 病变中高表达。此外，TWEAK 增强了 UVB 诱导的小鼠角质形成细胞中 Ro52 的上调。同时，TWEAK 刺激角质形成细胞，通过促进趋化因子 C-C 基序配体 17 和 22 的产生，有利于巨噬细胞的迁移。此外，Fn14 siRNA 转染或核因子-κ B (NF-κB) 抑制剂消除了 TWEAK 对角质形成细胞中 Ro52 表达的增强。同样，在 TWEAK 刺激后，TNF 受体相关因子 2 (TRAF2) siRNA 降低了这些细胞中 Ro52 的蛋白水平。有趣的是，UVB 照射增加了角质形成细胞中 1 型 TNF 受体 (TNFR1) 的表达，但不影响 TNFR2 的表达。总之，TWEAK/Fn14 信号传导参与 Ro52 介导的光敏化，并涉及 NF-κB 通路的激活以及 TRAF2/TNFR 伴侣的功能。
Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) binds to its sole receptor fibroblast growth factor-inducible 14 (Fn14), participating in various inflammatory responses. Recently, TWEAK/Fn14 activation was found prominent in the lesions of cutaneous lupus erythematosus (CLE). This study was designed to further reveal the potential role of this pathway in Ro52-mediated photosensitization. TWEAK, Fn14, and Ro52 were determined in the skin lesions of patients with CLE. Murine keratinocytes received ultraviolet B (UVB) irradiation or plus TWEAK stimulation and underwent detection for Ro52 and proinflammatory cytokines. The chemotaxis of J774.2 macrophages was evaluated on TWEAK stimulation of cocultured keratinocytes. We found that TWEAK, Fn14, and downstream cytokines were highly expressed in CLE lesions that overexpressed Ro52. Moreover, TWEAK enhanced the UVB-induced Ro52 upregulation in murine keratinocytes. Meanwhile, TWEAK stimulation of keratinocytes favored the migration of macrophages through promoting the production of chemokine C–C motif ligands 17 and 22. Furthermore, Fn14 siRNA transfection or nuclear factor-kappa B (NF-κB) inhibitor abrogated the TWEAK enhancement of Ro52 expression in keratinocytes. Similarly, TNF receptor associated factor 2 (TRAF2) siRNA reduced the protein level of Ro52 in these cells upon TWEAK stimulation. Interestingly, UVB irradiation increased the expression of TNF receptor type 1 (TNFR1) but not affecting TNFR2 expression in keratinocytes. In conclusion, the TWEAK/Fn14 signaling participates in Ro52-mediated photosensitization and involves the activation of NF-κB pathway as well as the function of the TRAF2/TNFR partners.