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Abstract：
The NLRP3 inflammasome is formed by the sensor NLRP3, the adaptor ASC, and pro-caspase-1. Assembly and activation of the inflammasome trigger caspase-1-dependent cleavage of pro-IL-1β and pro-IL-18 into their secreted forms. Cigarette smoke is a risk factor for chronic inflammatory diseases and is associated with macrophage dysfunction. The impact of cigarette smoke on NLRP3-dependent responses in macrophages is largely unknown. Herein, we investigated the effects of cigarette smoke extract (CSE) on the NLRP3 inflammasome in human monocyte-derived macrophages (MDMs) and THP-1 cells stimulated with lipopolysaccharide (LPS) and LPS plus the NLRP3 inflammasome activator ATP. We found that CSE inhibited the release of IL-1β and IL-18 as well as the expression of NLRP3 acting mainly at the transcriptional level. Interestingly, we found that CSE increased the caspase-1 activity via an NLRP3-independent and TLR4-TRIF-caspase-8-dependent pathway. Activation of caspase-1 by CSE led to a reduction of the basal glycolytic flux and impaired glycolytic burst in response to LPS. Overall, our findings unveil novel pathways leading to immune-metabolic alterations in human macrophages exposed to cigarette smoke. These mechanisms may contribute to macrophage dysfunction and increased risk of infection in smokers.
摘要：
NLRP3炎性体由传感器NLRP3，适配器ASC，和pro-caspase-1。炎性小体的组装和激活引发pro-IL-1β和pro-IL-18的caspase-1依赖性裂解为其分泌形式。香烟烟雾是慢性炎症性疾病的危险因素，并与巨噬细胞功能障碍有关。香烟烟雾对巨噬细胞中NLRP3依赖性反应的影响在很大程度上是未知的。在这里，我们研究了香烟烟雾提取物(CSE)对人单核细胞源性巨噬细胞(MDMs)和THP-1细胞中NLRP3炎性体的影响,这些细胞被脂多糖(LPS)和LPS加NLRP3炎性体激活剂ATP刺激.我们发现CSE主要在转录水平上抑制IL-1β和IL-18的释放以及NLRP3的表达。有趣的是,我们发现CSE通过NLRP3非依赖性和TLR4-TRIF-caspase-8依赖性途径增加caspase-1活性.CSE对半胱天冬酶-1的激活导致基础糖酵解通量的减少和响应于LPS的糖酵解爆发受损。总的来说,我们的发现揭示了导致暴露于香烟烟雾的人巨噬细胞免疫代谢改变的新途径.这些机制可能导致巨噬细胞功能障碍和吸烟者感染风险增加。
