Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD
Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD
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DOI：
10.1681/asn.2017080863
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发表时间：
2018-04-01
影响因子：
13.6
通讯作者：
Muruve, Daniel A.
中科院分区：
文献类型：
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作者：
Komada, Takanori;Chung, Hyunjae;Muruve, Daniel A.
非微生物炎症有助于慢性肾脏病的进展和纤维化。黑色素瘤缺失2(AIM2)是双链DNA的炎症体形成受体。AIM2在肾脏中表达，主要由巨噬细胞激活。我们研究了AIM2炎症小体在肾脏疾病中的潜在致病作用。在糖尿病或非糖尿病CKD患者的肾脏中，免疫荧光显示AIM2在肾小球、肾小管和浸润性白细胞中表达。在单侧输尿管梗阻(UUO)的小鼠模型中，AIM缺乏可减轻野生型(WT)仔鼠的肾脏损伤、纤维化和炎症。在骨髓嵌合体研究中，UUO在接受WT骨髓的AIM2(-/-)或WT小鼠中比接受AIM2(-/-)骨髓的WT小鼠诱导更多的肾小管损伤和IL-1β裂解。UUO后5-6天对LysM((GFP/GFP))小鼠肾脏的活体显微镜观察显示，GFP(+)促炎症巨噬细胞显著募集，沿着受损的小管爬行，吞噬坏死细胞中的DNA，并表达活性的caspase-1。DNA摄取发生在招募的巨噬细胞内的大空泡结构中，而不是常驻的CX(3)CR1(+)肾吞噬细胞中。在体外，吞噬坏死碎片的巨噬细胞显示出依赖于AIM2的caspase-1和IL-1β的激活，以及AIM(2+)ASC斑点的形成。ASC斑点是炎症体激活的标志。与DNasel共治疗可减轻IL-1β水平的升高，证实DNA是这一过程中主要的损伤相关分子模式。因此，AIM2炎症体被来自坏死细胞的DNA激活，驱动了促炎表型，从而导致肾脏的慢性损伤。
Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1 beta cleavage in Aim2(-/-) or WT mice that received WT bone marrow than in WT mice that received Aim2(-/-) bone marrow. Intravital microscopy of the kidney in LysM((gfp/gfp)) mice 5-6 days after UUO demonstrated the significant recruitment of GFP(+) proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX(3)CR1(+) renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1 beta, as well as the formation of AIM(2+) ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNasel attenuated the increase in IL-1 beta levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.