Bone Marrow-Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence-Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein-Interferon-β Feedback Loop.
Bone Marrow-Derived Mesenchymal Stem Cells From Patients With Systemic Lupus Erythematosus Have a Senescence-Associated Secretory Phenotype Mediated by a Mitochondrial Antiviral Signaling Protein-Interferon-β Feedback Loop.
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DOI：
10.1002/art.40142
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发表时间：
2017-08
期刊：
影响因子：
--
通讯作者：
Looney RJ
中科院分区：
文献类型：
--
作者：
Gao L;Bird AK;Meednu N;Dauenhauer K;Liesveld J;Anolik J;Looney RJ
骨髓间充质干细胞为造血和免疫创造了特殊的微环境，并表现出强大的免疫调节特性，这些特性在系统性红斑狼疮中受到损害。本研究旨在明确人系统性红斑狼疮骨髓间充质干细胞缺陷的机制。符合SLE分类标准的患者和健康对照按照机构审查委员会批准的方案招募(n=6)。用低密度Ficoll/Hypaque分离BMSCs。采用免疫细胞化学、实时定量聚合酶链式反应、免疫印迹、彗星试验、β-半乳糖苷酶试验和RNA干扰等方法对骨髓间充质干细胞进行鉴定。系统性红斑狼疮骨髓间充质干细胞具有衰老的表型，其特征是增殖率降低，产生的活性氧(ROS)增加，DNA损伤和修复增加，阻断细胞周期的p53和p16表达增加，细胞因子产生改变(促炎细胞因子增加，免疫调节细胞因子产生减少)。此外，系统性红斑狼疮骨髓间充质干细胞干扰素β的表达增加了5倍(p<；0.05)，干扰素β诱导的mRNAs的表达增加，包括细胞内核酸感受接头蛋白MAVs的β，其表达与干扰素mRNA量高度相关(r>；0.9，p<；0.01)。由于MAV可诱导干扰素β的产生，我们假设MAV与干扰素β之间存在正反馈循环。显著地，沉默MAV显著降低干扰素β、P53和p16的蛋白水平以及促炎细胞因子的mRNAs的表达。本研究证明了一种新的途径，使干扰素β信号在系统性红斑狼疮中升高，它不依赖于免疫复合体的刺激，而是由干扰素β和MAV介导的细胞固有的，这意味着新的途径可能成为潜在的治疗靶点。
BMSCs create a special microenvironment for hematopoiesis and immunity and also display robust immunomodulatory properties which are impaired in SLE. This study was undertaken to define the mechanisms of defects in human SLE BMSCs. Patients fulfilling SLE classification criteria and healthy controls were recruited under an Institutional Review Board approved protocol (n=6 each). BMSCs were isolated with low density Ficoll/Hypaque. BMSCs were verified by flow cytometry and studied using immunocytochemistry, real-time PCR, western blotting, comet assay, beta-galactosidase assay, and RNA interference. SLE BMSCs have a senescent phenotype characterized by reduced proliferation rate, increased production of reactive oxygen species (ROS), increased DNA damage and repair, increased expression of p53 and p16 which block the cell cycle, and altered cytokine production (increased pro-inflammatory cytokine and decreased immunomodulatory cytokine production). Moreover, SLE BMSCs have a 5 fold increase in IFNβ (p<0.05) and increased IFNβ-induced mRNAs including mRNA for the intracellular nucleic acid sensing adaptor protein MAVS whose expression was highly correlated with IFNβ levels (r > 0.9, p < 0.01). Since MAVS is known to induce IFNβ production, we hypothesized a positive feedback loop between MAVS and IFNβ. Strikingly, silencing MAVS markedly decreased IFNβ, p53, and p16 protein levels and expression of mRNAs for pro-inflammatory cytokines. This study demonstrates a novel pathway for elevated IFNβ signaling in SLE that is not dependent on stimulation by immune complexes but rather is cell-intrinsic and critically mediated by IFNβ and MAVS, implicating new pathways as potential therapeutic targets.
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影响因子：
64.5
作者：
López-Otín C;Blasco MA;Partridge L;Serrano M;Kroemer G
通讯作者：
Kroemer G
影响因子：
13.3
作者：
Chiche, Laurent;Jourde-Chiche, Noemie;Whalen, Elizabeth;Presnell, Scott;Gersuk, Vivian;Dang, Kristen;Anguiano, Esperanza;Quinn, Charlie;Burtey, Stephane;Berland, Yvon;Kaplanski, Gilles;Harle, Jean-Robert;Pascual, Virginia;Chaussabel, Damien
通讯作者：
Chaussabel, Damien
影响因子：
3.3
作者：
Moiseeva, O;Mallette, FA;Ferbeyre, G
通讯作者：
Ferbeyre, G
DOI：
10.1073/pnas.92.20.9363
发表时间：
1995-09-26
影响因子：
11.1
作者：
DIMRI, GP;LEE, XH;CAMPISI, J
通讯作者：
CAMPISI, J
影响因子：
2.8
作者：
Liu, Xiaowen;Jiao, Yulian;Zhao, Yueran
通讯作者：
Zhao, Yueran