Inflammasomes in COPD and neutrophilic asthma
Inflammasomes in COPD and neutrophilic asthma
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DOI：
10.1136/thoraxjnl-2014-206736
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发表时间：
2015-12-01
期刊：
影响因子：
10
通讯作者：
Hansbro, Philip M.
中科院分区：
文献类型：
--
作者：
Kim, Richard Y.;Pinkerton, James W.;Hansbro, Philip M.
炎性小体最近已被鉴定为炎症的关键和有效的诱导剂，当其过度活跃时，可以在炎性疾病中进行治疗靶向。炎性小体是多蛋白信号传导复合物，其控制促炎细胞因子的成熟和释放以响应许多外源性、内源性和致病性危险信号（图1）。1它们介导宿主反应，特别是白细胞介素（IL）-1β释放和嗜酸性炎症反应，这对于保护免受感染至关重要。然而，最近的证据表明，过度的炎性小体活化是许多炎性疾病的特征，包括COPD、嗜酸性哮喘、特发性肺纤维化、囊性纤维化、急性呼吸窘迫综合征（ARDS）和呼吸道感染（图1中的表格）。感染是炎性小体最广泛认可的激活剂;然而，这一领域最近已被广泛审查，超出了本文的范围。它们在ARDS中的作用和治疗靶向的潜力已经得到了很好的确立。2目前发现炎性小体可能参与COPD和哮喘的发病机制，迫切需要进一步研究。迄今为止，已经鉴定出五种主要的炎性小体：NLRP 1、NLRC 4、RIG-1、AIM 2和NLRP 3。它们与称为衔接蛋白的其他蛋白质相互作用，这些蛋白质包含胱天蛋白酶募集结构域（ASC）和胱天蛋白酶原-1（pro-caspase-1），以形成不同的炎性小体复合物（图1）。炎性小体的表达、复合物形成和活化由危险信号引发，所述危险信号由在感染、损伤、炎症或应激期间释放的细菌组分（病原体相关分子模式（PAMP））和/或宿主衍生因子（损伤相关分子模式（DAMP））活化。炎性小体活化引发级联反应，导致半胱天冬酶原-1募集并裂解成活性半胱天冬酶-1分子，然后介导活化细胞内IL-1β原裂解成其活性形式IL-1β。也发生pro-IL-18裂解成活性IL-18。半胱天冬酶-1还触发称为焦亡的不受控制的细胞死亡形式，其导致促炎介质和其他细胞内容物释放到细胞外环境中，进一步诱导炎症反应。因此，炎性小体的活化对于诱导IL-1β的半胱天冬酶-1依赖性加工、成熟和分泌至关重要。这突出了炎性小体在IL-1β介导的免疫应答中的关键作用（图1）。1还有非炎性介导的机制激活和修饰IL-1β和IL-18应答，包括胱天蛋白酶-8和颗粒酶B，以及许多丝氨酸蛋白酶和类胰蛋白酶。然而，对这些的讨论超出了本综述的范围。在炎性小体中，NLRP 3的性质和功能是最好的特征。1 NLRP 3的表达、组装和pro-IL-1β的产生由一系列促炎信号传导事件诱导，例如由受体家族触发的那些，包括识别PAMP（如脂多糖和肽聚糖）的Toll样受体。1尽管在不存在PAMP的情况下可以观察到炎性小体依赖性caspase-1活化，但所产生的活性IL-1β水平极低。此外，组装的NLRP 3复合物的激活以及随后的caspase-1的产生需要DAMP的存在，例如细胞外ATP和甘油三酯晶体，这些晶体是由细胞在炎症条件下产生的。
Inflammasomes have recently been identified to be critical and potent inducers of inflammation that when overactive may be targeted therapeutically in inflammatory diseases. Inflammasomes are multiprotein signalling complexes that control the maturation and release of pro-inflammatory cytokines in response to numerous exogenous, endogenous and pathogenic danger signals (figure 1). 1 They mediate host responses, particularly interleukin (IL)-1β release and neutrophilic inflammatory responses, which are essential for protection against infection. However, recent evidence demonstrates that excessive inflammasome activation is a feature of numerous inflammatory diseases including COPD, neutrophilic asthma, idiopathic pulmonary fibrosis, cystic fibrosis, acute respiratory distress syndrome (ARDS) and respiratory infections (table in figure 1). Infections are the most widely recognised activators of inflammasomes; however, this field has recently been reviewed extensively and is beyond the scope of this article. Their roles in ARDS and potential for therapeutic targeting are well established. 2 It is now emerging that inflammasomes are likely involved in the pathogenesis of COPD and asthma, and further investigation is urgently needed. To date, five main inflammasomes have been identified; NLRP1, NLRC4, RIG-I, AIM2 and NLRP3. They interact with other proteins termed the adaptor protein apoptosis-associated speck-like containing a caspase recruitment domain (ASC) and pro-caspase-1 to form distinct inflammasome complexes (figure 1). The expression, complex formation and activation of inflammasomes are initiated by danger signals that are activated by bacterial components (pathogen-associated molecular patterns (PAMPs)) and/or host-derived factors (damage-associated molecular patterns (DAMPs)) that are released during infection, injury, inflammation or stress. Inflammasome activation initiates a cascade of events that result in the recruitment and cleavage of pro-caspase-1 into active caspase-1 molecules that then mediate the cleavage of pro-IL-1β into its active form, IL-1β, within the activated cell. Cleavage of pro-IL-18 into active IL-18 also occurs. Caspase-1 also triggers an uncontrolled form of cell death known as pyroptosis, which results in the release of pro-inflammatory mediators and other cellular contents into the extracellular environment, further inducing inflammatory responses. Therefore, activation of the inflammasome is crucial for the induction of caspase-1-dependent processing, maturation and secretion of IL-1β. This highlights a key role for the inflammasome in IL-1β-mediated immune responses (figure 1). 1 There are also non-inflammasomemediated mechanisms that activate and modify IL-1β and IL-18 responses including caspase-8 and granzyme B, and numerous serine proteases and tryptases. However, a discussion of these is outside the scope of this review.Of the inflammasomes, the properties and functions of NLRP3 are best characterised. 1 NLRP3 expression, assembly and the production of pro-IL-1β are induced by a range of pro-inflammatory signalling events, such as those triggered by families of receptors including the Toll-like receptors that recognise PAMPs such as lipopolysaccharide and peptidoglycan. 1 Although inflammasomedependent caspase-1 activation can be observed in the absence of PAMPs, the resulting levels of active IL-1β are minimal. 1 Furthermore, the activation of the assembled NLRP3 complex, and subsequent generation of caspase-1, requires the presence of DAMPs such as extracellular ATP and monosodium urate crystals, which are produced by cells under inflammatory …