Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity
Loss of Trex1 in Dendritic Cells Is Sufficient To Trigger Systemic Autoimmunity
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DOI：
10.4049/jimmunol.1600722
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发表时间：
2016-09-15
影响因子：
4.4
通讯作者：
Behrendt, Rayk
中科院分区：
文献类型：
--
作者：
Peschke, Katrin;Achleitner, Martin;Behrendt, Rayk
细胞内酶39修复核酸外切酶1（Trex 1）的缺陷导致罕见的自身免疫性疾病Aicardi-Goutie 'res综合征，并与系统性红斑狼疮有关。Trex 1（-/-）小鼠发生I型IFN驱动的自身免疫，这是由于Trex 1的核酸底物激活细胞质DNA传感器环GMP-AMP合酶所致，目前尚不清楚。为了鉴定负责启动自身免疫的细胞类型，我们产生了条件性Trex 1敲除小鼠。树突状细胞中Trex 1的缺失足以引起IFN释放和自身免疫，而Trex 1缺陷的角质形成细胞和小胶质细胞产生IFN，但不诱导炎症。相反，B细胞、心肌细胞、神经元和星形胶质细胞对Trex 1的失活没有表现出任何可检测的反应。因此，个别细胞类型对Trex 1的缺失有不同的反应，并且Trex 1在树突细胞中的表达对于防止内源性DNA的异常检测导致的自身耐受性的破坏是必不可少的。
Defects of the intracellular enzyme 39 repair exonuclease 1 (Trex1) cause the rare autoimmune condition Aicardi-Goutie` res syndrome and are associated with systemic lupus erythematosus. Trex1(-/-) mice develop type I IFN-driven autoimmunity, resulting from activation of the cytoplasmic DNA sensor cyclic GMP-AMP synthase by a nucleic acid substrate of Trex1 that remains unknown. To identify cell types responsible for initiation of autoimmunity, we generated conditional Trex1 knockout mice. Loss of Trex1 in dendritic cells was sufficient to cause IFN release and autoimmunity, whereas Trex1-deficient keratinocytes and microglia produced IFN but did not induce inflammation. In contrast, B cells, cardiomyocytes, neurons, and astrocytes did not show any detectable response to the inactivation of Trex1. Thus, individual cell types differentially respond to the loss of Trex1, and Trex1 expression in dendritic cells is essential to prevent breakdown of self-tolerance ensuing from aberrant detection of endogenous DNA.