DNA-dependent Activator of Interferon-regulatory Factors (DAI) Promotes Lupus Nephritis by Activating the Calcium Pathway*
DNA-dependent Activator of Interferon-regulatory Factors (DAI) Promotes Lupus Nephritis by Activating the Calcium Pathway*
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DOI：
10.1074/jbc.m113.457218
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发表时间：
2013-04
期刊：
影响因子：
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通讯作者：
Weijuan Zhang;Qian Zhou;Wei Xu;Yanxing Cai;Z. Yin;Xiaoming Gao;S. Xiong
中科院分区：
文献类型：
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作者：
Weijuan Zhang;Qian Zhou;Wei Xu;Yanxing Cai;Z. Yin;Xiaoming Gao;S. Xiong
背景：自身DNA免疫引起的巨噬细胞M2 b极化启动并传播狼疮性肾炎。结果如下：干扰素调节因子（DAI）的DNA依赖性激活剂的敲低通过钝化巨噬细胞M2 b极化来改善SLE综合征。结论：DAI在自身DNA诱导的巨噬细胞M2 b极化和狼疮性肾炎中起DNA传感器的作用。意义：我们揭示了自身DNA诱导巨噬细胞M2 b极化和狼疮性肾炎的机制。干扰素调节因子（DAI）的DNA依赖性激活剂作为激活先天免疫系统的细胞质DNA传感器起作用。我们以前发现，活化的淋巴细胞衍生的自凋亡DNA（ALD-DNA）免疫导致病理性巨噬细胞活化和M2 b极化，这可以启动和传播小鼠狼疮肾炎。然而，系统性红斑狼疮（SLE）疾病中ALD-DNA诱导的巨噬细胞M2 b极化的特异性DNA传感器以及潜在的分子机制仍然未知。在这项研究中，我们报告说，DAI表达显着增加SLE患者以及狼疮小鼠。获得和丧失功能的研究表明，DAI参与ALD-DNA诱导的巨噬细胞活化和M2 b极化。此外，ALD-DNA显著诱导DAI的二聚化/寡聚化，并因此通过钙信号传导激活核因子κB（NF-κB）和干扰素调节因子3（IRF 3）信号传导途径，导致巨噬细胞活化和M2 B极化。更重要的是，在体内阻断DAI或选择性敲低巨噬细胞中的DAI可以通过钝化巨噬细胞M2 b极化和抑制狼疮小鼠的炎症反应来改善SLE综合征。结果提示DAI在ALD-DNA诱导的巨噬细胞M2 b极化和狼疮性肾炎中起DNA传感器和调节剂的作用，为阐明ALD-DNA诱导的巨噬细胞M2 b极化在SLE疾病中的可能分子机制提供了理论依据，并使DAI成为SLE治疗的潜在靶点。
Background: Macrophage M2b polarization conferred by self-DNA immunization initiates and propagates lupus nephritis. Results: Knockdown of DNA-dependent activator of interferon-regulatory factors (DAI) ameliorates SLE syndrome via blunting macrophage M2b polarization. Conclusion: DAI functions as a DNA sensor in self-DNA-induced macrophage M2b polarization and lupus nephritis. Significance: We disclose the mechanism by which self-DNA induces macrophage M2b polarization and lupus nephritis. DNA-dependent activator of interferon-regulatory factors (DAI) functions as a cytoplasmic DNA sensor that activates the innate immune system. We previously found that activated lymphocyte-derived self-apoptotic DNA (ALD-DNA) immunization led to pathological macrophage activation and M2b polarization, which could initiate and propagate murine lupus nephritis. However, the specific DNA sensor(s) as well as underlying molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in systemic lupus erythematosus (SLE) disease remains unknown. In this study, we reported that DAI expression was significantly increased in SLE patients as well as in lupus mice. Gain- and loss-of-function studies revealed that DAI was involved in ALD-DNA-induced macrophage activation and M2b polarization. Moreover, ALD-DNA notably induced dimerization/oligomerization of DAI and consequently activation of nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF3) signaling pathways via calcium signaling, resulting in macrophage activation and M2b polarization. More importantly, blockade of DAI in vivo or selective knockdown of DAI in macrophages could ameliorate SLE syndrome via blunting macrophage M2b polarization and inhibiting inflammatory response in lupus mice. Our results suggest that DAI could function as a DNA sensor and a regulator in ALD-DNA-induced macrophage M2b polarization and lupus nephritis, providing the possible molecular mechanisms involved in ALD-DNA-induced macrophage M2b polarization in SLE disease and making DAI as a potential therapeutic target for the treatment of SLE.