Inflammasomes

In contrast to NOD1/2 some NLRPs function as large macromolecular complexes called 'Inflammasomes'. These multiprotein platforms control activation of the cysteinyl aspartate protease caspase-1 and thereby the subsequent cleavage of pro-interleukin 1B (pro-IL1B) into the active proinflammatory cytokine IL1B. Activation of caspase-1 is essential for production of IL1B and IL18, which respectively bind and activate the IL1 receptor (IL1R) and IL18 receptor (IL18R) complexes. IL1R and IL18R activate NFkappaB and other signaling cascades.<br><br>As the activation of inflammasomes leads to caspase-1 activation, inflammasomes can be considered an upstream step of the IL1R and IL18R signaling cascades, linking intracellular pathogen sensing to immune response pathways mediated by Toll-Like Receptors (TLRs). Monocytes and macrophages do not express pro-IL1B until stimulated, typically by TLRs (Franchi et al. 2009). The resulting pro-IL1B is not converted to IL1B unless a second stimulus activates an inflammasome. This requirement for two distinct stimuli allows tight regulation of IL1B/IL18 production, necessary because excessive IL-1B production is associated with numerous inflammatory diseases such as gout and rheumatoid arthritis (Masters et al. 2009).<br><br>There are at least four subtypes of the inflammasome, characterized by the NLRP. In addition the protein AIM2 can form an inflammasome. All activate caspase-1. NLRP1 (NALP1), NLRP3 (Cryopyrin, NALP3), IPAF (CARD12, NLRC4) and AIM2 inflammasomes all have clear physiological roles in vivo. NLRP2, NLRP6, NLRP7, NLRP10 and NLRP12 have been demonstrated to modulate caspase-1 activity in vitro but the significance of this is unclear (Mariathasan and Monack, 2007).<br><br>NLRP3 and AIM2 bind the protein 'apoptosis-associated speck-like protein containing a CARD' (ASC, also called PYCARD), via a PYD-PYD domain interaction. This in turn recruits procaspase-1 through a CARD-CARD interaction. NLRP1 and IPAF contain CARD domains and can bind procaspase-1 directly, though both are stimulated by ASC. Oligomerization of NLRPs is believed to bring procaspases into close proximity, leading to 'induced proximity' auto-activation (Boatright et al. 2003). This leads to formation of the active caspase tetramer. NLRPs are generally considered to be cytoplasmic proteins, but there is evidence for cytoplasmic-nuclear shuttling of the family member CIITA (LeibundGut-Landmann et al. 2004) and tissue/cell dependent NALP1 expression in the nucleus of neurons and lymphocytes (Kummer et al. 2007); the significance of this remains unclear.

与NOD1/2不同，某些NLRP蛋白充当被称为'炎症小体'的巨大大分子复合体。这些多蛋白平台调控半胱氨酸天冬氨酸蛋白酶caspase-1的活化，进而导致前白介素1B（pro-IL1B）被切割成活性前炎症细胞因子IL1B。caspase-1的活化对于IL1B和IL18的产生至关重要，它们分别与IL1受体（IL1R）和IL18受体（IL18R）复合物结合并活化。IL1R和IL18R激活NFkappaB和其他信号级联反应。<br><br>由于炎症小体的活化导致caspase-1的活化，因此炎症小体可以被视为IL1R和IL18R信号级联的上游步骤，将细胞内病原体感知与通过Toll样受体（TLRs）介导的免疫反应途径联系起来。单核细胞和巨噬细胞在受到刺激之前不表达pro-IL1B，通常由TLRs（Franchi等，2009年）刺激。除非第二个刺激激活炎症小体，否则产生的pro-IL1B不会转化为IL1B。这种对两个不同刺激的需求允许对IL1B/IL18的产生进行严格的调控，这是必要的，因为IL-1B的产生过多与痛风和类风湿性关节炎等多种炎症性疾病相关（Masters等，2009年）。<br><br>至少存在四种炎症小体亚型，以NLRP为特征。此外，蛋白质AIM2可以形成炎症小体。所有这些炎症小体都能激活caspase-1。NLRP1（NALP1）、NLRP3（Cryopyrin，NALP3）、IPAF（CARD12，NLRC4）和AIM2炎症小体在体内都具有明确的生理作用。NLRP2、NLRP6、NLRP7、NLRP10和NLRP12已被证明在体外调节caspase-1的活性，但其意义尚不清楚（Mariathasan和Monack，2007年）。<br><br>NLRP3和AIM2通过PYD-PYD结构域相互作用与蛋白质'凋亡相关斑点样蛋白含有CARD'（ASC，也称为PYCARD）结合。这反过来又通过CARD-CARD相互作用募集procaspase-1。NLRP1和IPAF含有CARD结构域，可以直接结合procaspase-1，尽管两者都受到ASC的刺激。NLRPs的寡聚化被认为将procaspases拉近，导致'诱导邻近'自活化（Boatright等，2003年）。这导致活性caspase四聚体的形成。NLRPs通常被认为是细胞质蛋白，但有关该家族成员CIITA（LeibundGut-Landmann等，2004年）的细胞质-核穿梭以及神经元和淋巴细胞核中组织/细胞依赖性NALP1表达的证据存在；其意义尚不明确。