第二型纖溶酶原激活物抑制酶經由引發自噬作用和NLRP3降解作用以抑制類鐸受體引發之介白素-1β產生

Abstract

NLRP3 inflammasome 是一種透過辨識廣泛的外來病原或身體內部損傷因子而活化形成的複合蛋白體，它進而促使半胱氨酸蛋白酶-1的活化及前發炎性細胞激素的介白素-1β 和 -18的產生。 在許多致病性的疾病中，可以發現NLRP3 inflammasome 的功能失調以致過度活化，但是它的調節機制仍舊不是很清楚。 在這裡我們發現在巨噬細胞內剔除一種絲胺酸蛋白酶抑制素，第二型纖溶酶原激活物抑制酶，再活化類鐸受體4和2的訊息傳導過程會造成 NLRP3和 ASC控制的半胱氨酸蛋白酶-1的活化及介白素-1β 的大量產生。然而活化類鐸受體4和2 也會誘導第二型纖溶酶原激活物抑制酶的表現，它會穩定自噬基因蛋白Beclin 1，進而促使自噬作用的增加來降低粒線體的自由基的產生、NLRP3蛋白質的表現及前介白素-1β的生產作用。由我們的實驗確立了一個藉由活化類鐸受體的訊號傳導中來調控NLRP3 inflammasome的活性，並揭示了一種新的細胞自主機制去負調節經由類鐸受體或大腸桿菌所引起的線粒體功能障礙、氧化壓力和介白素-1β 所產生的發炎反應。

The NLRP3 inflammasome, a multiprotein complex, triggers caspase-1 activation and maturation of proinflammatory cytokines IL-1β and IL-18 upon sensing a wide range of pathogen- and damage-associated molecules. Dyregulation of the NLRP3 inflammasome activity contributes to the pathogenesis of many diseases, but its regulation remains poorly defined. Here we show that depletion of Plasminogen activator inhibitor type 2 (PAI-2), a serine protease inhibitor, resulted in NLRP3- and ASC-dependent caspase-1 activation and IL-1β secretion in macrophages upon TLR2 and TLR4 engagement. TLR2 or 4 agonists induced PAI-2 expression, which subsequently stabilized autophagic protein Beclin 1 to promote autophagy resulting in decreased mitochondrial reactive oxygen species (mROS), NLRP3 protein as well as pro-IL-1β processing. Together, our data identify a new tier of TLR signaling in controlling NLRP3 inflammasome activation, and reveal a novel cell-autonomous mechanism which inversely regulates TLRs- or Escherichia coli-induced mitochondrial dysfunction, oxidative stress, and IL-1β-driven inflammation.