Wihuri Research Institute, 00140 Helsinki, Finland.
J Immunol. 2011 Jun 1;186(11):6119-28. doi: 10.4049/jimmunol.1002843. Epub 2011 Apr 20.
Serum amyloid A (SAA) is an acute-phase protein, the serum levels of which can increase up to 1000-fold during inflammation. SAA has a pathogenic role in amyloid A-type amyloidosis, and increased serum levels of SAA correlate with the risk for cardiovascular diseases. IL-1β is a key proinflammatory cytokine, and its secretion is strictly controlled by the inflammasomes. We studied the role of SAA in the regulation of IL-1β production and activation of the inflammasome cascade in human and mouse macrophages, as well as in THP-1 cells. SAA could provide a signal for the induction of pro-IL-1β expression and for inflammasome activation, resulting in secretion of mature IL-1β. Blocking TLR2 and TLR4 attenuated SAA-induced expression of IL1B, whereas inhibition of caspase-1 and the ATP receptor P2X(7) abrogated the release of mature IL-1β. NLRP3 inflammasome consists of the NLRP3 receptor and the adaptor protein apoptosis-associated speck-like protein containing CARD (a caspase-recruitment domain) (ASC). SAA-mediated IL-1β secretion was markedly reduced in ASC(-/-) macrophages, and silencing NLRP3 decreased IL-1β secretion, confirming NLRP3 as the SAA-responsive inflammasome. Inflammasome activation was dependent on cathepsin B activity, but it was not associated with lysosomal destabilization. SAA also induced secretion of cathepsin B and ASC. In conclusion, SAA can induce the expression of pro-IL-1β and activation of the NLRP3 inflammasome via P2X(7) receptor and a cathepsin B-sensitive pathway. Thus, during systemic inflammation, SAA may promote the production of IL-1β in tissues. Furthermore, the SAA-induced secretion of active cathepsin B may lead to extracellular processing of SAA and, thus, potentially to the development of amyloid A amyloidosis.
血清淀粉样蛋白 A (SAA) 是一种急性期蛋白，在炎症期间其血清水平可升高至 1000 倍。SAA 在淀粉样 A 型淀粉样变性中具有致病性作用，并且 SAA 血清水平升高与心血管疾病的风险相关。IL-1β 是一种关键的促炎细胞因子，其分泌受到炎症小体的严格控制。我们研究了 SAA 在人源和鼠源巨噬细胞以及 THP-1 细胞中调节 IL-1β 产生和激活炎症小体级联反应中的作用。SAA 可以提供诱导 pro-IL-1β 表达和炎症小体激活的信号，导致成熟的 IL-1β 分泌。阻断 TLR2 和 TLR4 可减弱 SAA 诱导的 IL1B 表达，而抑制 caspase-1 和 ATP 受体 P2X(7) 则消除了成熟的 IL-1β 的释放。NLRP3 炎症小体由 NLRP3 受体和包含半胱氨酸天冬氨酸蛋白酶募集结构域（caspase-recruitment domain，CARD）的凋亡相关斑点样蛋白（apoptosis-associated speck-like protein containing CARD，ASC）组成。在 ASC(-/-)巨噬细胞中，SAA 介导的 IL-1β 分泌明显减少，而沉默 NLRP3 则减少了 IL-1β 的分泌，证实 NLRP3 是 SAA 反应性炎症小体。炎症小体的激活依赖于组织蛋白酶 B 的活性，但与溶酶体不稳定无关。SAA 还诱导组织蛋白酶 B 和 ASC 的分泌。总之，SAA 可以通过 P2X(7)受体和组织蛋白酶 B 敏感途径诱导 pro-IL-1β 的表达和 NLRP3 炎症小体的激活。因此，在全身炎症期间，SAA 可能会促进组织中 IL-1β 的产生。此外，SAA 诱导的活性组织蛋白酶 B 的分泌可能导致 SAA 的细胞外加工，从而可能导致淀粉样 A 型淀粉样变性的发生。
