Identification of Interleukin-1β-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease.
Identification of Interleukin-1β-Producing Monocytes That Are Susceptible to Pyronecrotic Cell Death in Patients With Neonatal-Onset Multisystem Inflammatory Disease.
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鉴定新生儿发作多系统炎症性疾病的患者易受吡张单位性细胞死亡易感的白细胞介素1β产生的单核细胞。
DOI：
10.1002/art.39307
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发表时间：
2015-12
期刊：
影响因子：
--
通讯作者：
Colbert RA
中科院分区：
文献类型：
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作者：
Edwan JH;Goldbach-Mansky R;Colbert RA
由NLRP3基因突变引发的自发炎症反应促进炎症体介导的IL-1β的处理和释放，并可诱导迅速的坏死细胞死亡。新生儿多系统炎症性疾病中产生IL-1β的细胞尚不清楚，其介导IL-1β释放和细胞死亡的机制也尚未完全阐明。在组织蛋白酶B和caspase-1抑制剂存在的情况下，用脂多糖刺激全血细胞，然后用三磷酸腺苷处理。收集上清液，与IL-1β捕捉珠孵育。对细胞进行固定、渗透和细胞表面和细胞内标记相结合的染色，并使用一种新的基于微球的流式细胞术检测分泌的IL-1β。用免疫荧光显微镜对脂多糖刺激的细胞进行鉴定。以CD14hi、CD16低表达和细胞内CD83为特征的单核细胞在NOMID患者中表达增加，并负责对内毒素刺激的大部分IL-1β的产生。这群单核细胞也经历了单独内毒素的快速死亡反应，这种反应与IL-1、β和Asc的释放有关，具有嗜热性而不是嗜热性细胞死亡的特征。抑制细胞死亡可减少诺米德患者细胞产生的IL-1β。此外，IL-1还触发NOMID患者单核细胞的细胞死亡。这些结果确定单核细胞是NOMID患者外周血中主要的IL-1β产生细胞群。此外，他们提出，IL-1受体的阻断可能部分通过防止肾小球坏死细胞死亡来发挥作用，这可能是NOMID和其他形式的低温比林相关周期性综合征的一个重要靶点。
Spontaneous inflammatory responses initiated by NLRP3 mutations promote inflammasome-mediated IL-1β processing and release, and can induce rapid necrotic cell death. The cells that produce IL-1β in neonatal onset multisystem inflammatory disease (NOMID) have not been clearly identified, nor have the mechanisms mediating IL-1β release and cell death been completely elucidated. Whole blood cells were stimulated with LPS in the presence of cathepsin B and caspase-1 inhibitors, followed by ATP treatment. Supernatants were collected and incubated with IL-1β capturing beads. Cells were fixed, permeabilized and stained for a combination of cell surface and intracellular markers, and a novel flow cytometry bead-based assay was used to measure secreted IL-1β. LPS stimulated cells were also evaluated using immunofluorescence microscopy. Monocytes characterized by CD14hi CD16low expression and intracellular CD83 are increased in NOMID subjects and are responsible for the majority of IL-1β production in response to LPS stimulation. This population of monocytes also undergoes a rapid death response with LPS alone that is temporally associated with IL-1β and ASC release and has characteristic features of pyronecrotic but not pyroptotic cell death. Inhibition of cell death reduces IL-1β production from NOMID patient cells. In addition, IL-1 triggers cell death in monocytes from NOMID patients. These results identify monocytes as the predominant IL-1β-producing cell population in the peripheral blood of NOMID patients. Furthermore, they suggest that IL-1 receptor blockade may work in part by preventing pyronecrotic cell death, which may be an important target in NOMID and other forms of cryopyrin-associated periodic syndromes.
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影响因子：
29.7
作者：
Davis BK;Wen H;Ting JP
通讯作者：
Ting JP
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
影响因子：
3.6
作者：
Brennan, MA;Cookson, BT
通讯作者：
Cookson, BT
适配器 ASC 具有传播炎症的细胞外活性和“prionoid”活性。
影响因子：
30.5
作者：
通讯作者：
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影响因子：
30.5
作者：
通讯作者：
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