TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.
TLR4-Upregulated IL-1β and IL-1RI Promote Alveolar Macrophage Pyroptosis and Lung Inflammation through an Autocrine Mechanism.
复制标题
TLR4 上调 IL-1β 和 IL-1RI 通过自分泌机制促进肺泡巨噬细胞焦亡和肺部炎症
DOI：
10.1038/srep31663
复制
发表时间：
2016-08-16
影响因子：
4.6
通讯作者：
Fan J
中科院分区：
文献类型：
--
作者：
He X;Qian Y;Li Z;Fan EK;Li Y;Wu L;Billiar TR;Wilson MA;Shi X;Fan J
急性肺损伤（acute lung injury，ALI）是肺部感染后多器官功能障碍综合征（multiple organ dysfunction syndrome，MODS）的重要组成部分。肺泡巨噬细胞（Alveolar macrophages，AM）是ALI发病机制的核心。白细胞介素-1 β（IL-1β）是重要的促炎介质之一，其成熟受炎性小体的形成和激活的严格控制。IL-1β的生物学效应是通过IL-1受体（IL-1 R）介导的。在这项研究中，我们研究了LPS诱导的IL-1β释放和IL-1 RI上调对肺部炎症发展的影响。结果表明，在AM中，LPS-TLR 4信号不仅激活Nlrp 3炎性小体的活化和随后IL-1β的释放，而且通过MyD 88和NF-κB依赖性信号上调AM表面IL-1 RI的表达。因此，上调的IL-1 RI使AM对IL-1β敏感，并导致焦凋亡体形成，这反过来又导致AM焦凋亡，一种caspase-1依赖性炎性细胞死亡。我们进一步表明AM焦亡加重了肺部炎症。本研究证实了LPS诱导的先天性免疫的一种新机制，即IL-1β-IL-1 RI信号的继发性上调是LPS引起AM焦亡和肺损伤的原因。
Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome (MODS) following pulmonary infection. Alveolar macrophages (AM) are at the center of the pathogenesis of the development of ALI. Interleukin-1β (IL-1β) is one of the key pro-inflammatory mediators, and its maturation is tightly controlled by the formation and activation of the inflammasome. The biological effects of IL-1β are mediated through IL-1 receptor (IL-1R). In this study, we investigated the influence of LPS-induced IL-1β release and IL-1RI upregulation on the development of lung inflammation. We demonstrated that in AM, LPS-TLR4 signaling not only activates Nlrp3 inflammasome activation and subsequent release of IL-1β, but also up-regulates IL-1RI expression on AM surface through MyD88 and NF-κB dependent signaling. The upregulated IL-1RI, therefore, sensitizes AM to IL-1β and results in pyroptosome formation, which in turn leads to AM pyroptosis, a type of caspase-1-dependent inflammatory cell death. We further showed that AM pyroptosis exaggerates lung inflammation. The present study demonstrates a novel mechanism underlying LPS-induced innate immunity; that is, a secondary upregulation of IL-1β-IL-1RI signaling is responsible for AM pyroptosis and augmented lung injury in response to LPS.