Poly(ADP-Ribose) Polymerase Enhances Infiltration of Mononuclear Cells in Primary Sjogren's Syndrome Through Interferon-Induced Protein With Tetratricopeptide Repeats 1-Mediated Up-Regulation of CXCL10
Poly(ADP-Ribose) Polymerase Enhances Infiltration of Mononuclear Cells in Primary Sjogren's Syndrome Through Interferon-Induced Protein With Tetratricopeptide Repeats 1-Mediated Up-Regulation of CXCL10
复制标题
聚（ADP-核糖）聚合酶通过干扰素诱导蛋白与四三肽重复 1 介导的 CXCL10 上调增强原发性干燥综合征中单核细胞的浸润
DOI：
10.1002/art.41195
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发表时间：
2020
影响因子：
13.3
通讯作者：
Wang Jianguang
中科院分区：
文献类型：
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作者：
Tian Qingqing;Zhao Han;Ling Hanzhi;Sun Li;Xiao Chipeng;Yin Guoyu;Wang Xiaobing;Wu Gan;Yang Chenglin;Chen Mu;Jin Shengwei;Yang Xinyu;Wang Jianguang
单核细胞浸润和I型干扰素（IFN）系统激活在原发性干燥综合征（SS）中起重要作用。我们进行了这项研究，以探讨机制的聚（ADP-核糖）聚合酶家族成员9（PARP-9）对单核细胞浸润触发的I型IFN.MethodsA蛋白质组学研究进行了外周血单核细胞从原发性SS患者（n = 30）和健康对照组（n = 30），以确定差异表达的蛋白质（DEP）（P< 0.05;倍数变化>1.20）。分离唇唾液腺（LSG）进行苏木精-伊红染色和免疫组织化学分析。通过磁性细胞分选纯化CD 19 + B细胞，用于免疫荧光染色、慢病毒-PARP-9转染和IFNα处理实验。将PARP-9小干扰RNA（siRNA）和DTX 3L siRNA分别导入NOD/LtJ雌性小鼠体内，观察其作用。在原发性SS患者中，LSG中的PARP-9水平随着奇泽姆评分的增加而升高。PARP-9和DTX 3L存在于雌性NOD/LtJ小鼠模型中唾液腺的浸润单核细胞中。此外，DEP的免疫途径分析网络表明，PARP-9、STAT 1和IFN-诱导的三肽重复序列1（IFIT-1）蛋白参与了IFN-相关途径。此外，PARP-9可上调B细胞中IFIT 1和CXCL 10的表达。结论本研究首次发现PARP-9是原发性SS进展中B细胞浸润的调节因子，并揭示PARP-9通过上调IFIT-1（由STAT 1磷酸化介导）增加CXCL 10的表达。因此，PARP-9可能是原发性SS的新治疗靶点。
ObjectiveMononuclear cell infiltration and type I interferon (IFN) system activation play an important role in primary Sjögren's syndrome (SS). We undertook this study to investigate the mechanism of poly(ADP‐ribose) polymerase family member 9 (PARP‐9) on mononuclear cell infiltration triggered by type I IFN.MethodsA proteomic study was conducted in peripheral blood mononuclear cells from patients with primary SS (n = 30) and healthy controls (n = 30) to determine differentially expressed proteins (DEPs) (P< 0.05; fold change >1.20). Labial salivary glands (LSGs) were isolated for hematoxylin and eosin staining and immunohistochemical analysis. CD19+ B cells were purified by magnetic cell sorting for immunofluorescence staining, lentivirus–PARP‐9 transfection, and IFNα treatment experiments. PARP‐9 small interfering RNA (siRNA) and DTX3L siRNA were delivered into female NOD/LtJ female mice to determine their effect.ResultsThe overexpression of PARP‐9 and CXCL10 as well as their colocalization was confirmed in primary SS. PARP‐9 levels in LSGs rose with increased Chisholm scores in patients with primary SS. PARP‐9 and DTX3L were present in the infiltrating mononuclear cells from salivary glands in female NOD/LtJ mouse models. Additionally, Ingenuity Pathway Analysis networks of DEPs demonstrated that PARP‐9, STAT1, and IFN‐induced protein with tetratricopeptide repeats 1 (IFIT‐1) participated in the IFN‐related pathway. Furthermore, PARP‐9 could up‐regulate the expression of IFIT1 and CXCL10 in B cells. Moreover, PARP‐9 and CXCL10 could be induced by IFNα in B cells.ConclusionThis study is the first to implicate PARP‐9 as a regulator of infiltration of mononuclear cells in primary SS progression and to reveal that PARP‐9 increases CXCL10 expression through up‐regulating IFIT‐1, which is mediated by the phosphorylation of STAT1. PARP‐9 might therefore be a novel therapeutic target for primary SS.