AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation
AIM2 Facilitates the Apoptotic DNA-induced Systemic Lupus Erythematosus via Arbitrating Macrophage Functional Maturation
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DOI：
10.1007/s10875-013-9881-6
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发表时间：
2013-07-01
影响因子：
9.1
通讯作者：
Xiong, Sidong
中科院分区：
文献类型：
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作者：
Zhang, Weijuan;Cai, Yanxing;Xiong, Sidong
目的狼疮性肾炎是系统性红斑狼疮(SLE)患者发病的主要原因之一，通常认为是由于各种自身抗体沉积在肾脏后，巨噬细胞介导的炎症所致。我们先前报道，活化的淋巴细胞源的凋亡DNA(ApopDNA)诱导的巨噬细胞异常激活在狼疮性肾炎的免疫失调中起致病作用。然而，DNA传感器(S)在凋亡素DNA诱导的巨噬细胞活化和狼疮性肾炎中的作用在很大程度上仍不清楚。方法分析系统性红斑狼疮患者及狼疮小鼠体内炎性小体途径胞浆DNA受体AIM2的表达水平与SLE疾病严重程度的相关性。用实时荧光定量聚合酶链式反应和免疫印迹法检测apopDNA诱导的巨噬细胞AIM2的表达。结果在SLE患者和狼疮小鼠中，AIM2的表达与疾病严重程度密切相关。重要的是，在apopDNA诱导的巨噬细胞中，AIM2的表达显著增加，并与巨噬细胞的激活密切相关。AIM2基因的敲除可显著抑制apopDNA诱导的巨噬细胞活化。此外，阻断AIM2的表达可通过抑制AopDNA诱导的狼疮小鼠的巨噬细胞活化和抑制炎症反应而显著改善SLE综合征。结论AIM2可能是AopDNA诱导的巨噬细胞功能成熟和SLE疾病的重要DNA感受器和潜在的生物标志物。
Purpose Lupus nephritis, a major cause of morbidity in patients with systemic lupus erythematosus (SLE), is generally thought to be induced by macrophage-mediated inflammation following deposition of various autoantibodies in kidneys. We previously reported that macrophage aberrant activation induced by activated lymphocyte-derived apoptotic DNA (apopDNA) have been found to play pathogenic roles in the immunodysregulation in lupus nephritis. However, DNA sensor(s) involved in apopDNA-induced macrophage activation and lupus nephritis remains largely undefined. Herein, we aimed to reveal the DNA sensor(s) involved in SLE disease.Methods Correlation between the level of absent in melanoma 2 (AIM2), a cytoplasmic DNA receptor in the inflammasome pathway, and the clinical severity of SLE disease were analyzed in SLE patients as well as in lupus mice. Activated macrophages induced by apopDNA were analyzed by real-time PCR and western blot for AIM2 expression. After silencing of AIM2 via siRNA-mediated knockdown in vitro and in vivo, macrophage activation, inflammatory response, and SLE syndrome were assessed.Results AIM2 expression was closely correlated with the severity of disease in SLE patients and in lupus mice. Importantly, AIM2 expression was significantly increased in apopDNA-induced macrophages and closely correlated with macrophage activation. Knockdown of AIM2 significantly blunted apopDNA-induced macrophage activation. Furthermore, blockade of AIM2 expression notably ameliorated SLE syndrome via impeding macrophage activation and dampening inflammatory response in apopDNA-induced lupus mice.Conclusions Our results implied that AIM2 might act as an important DNA sensor and a potential biomarker for apopDNA-induced macrophage functional maturation and SLE disease.