炎症体
细胞生物学
分泌物
生物
活性氧
信号转导衔接蛋白
半胱氨酸蛋白酶1
吡喃结构域
NLRC4型
受体
信号转导
生物化学
作者
Sang Hyeon Yeon,Gabsik Yang,Hye‐Eun Lee,Joo Young Lee
标识
DOI:10.1189/jlb.3vma1215-579rr
摘要
The NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome is a multiprotein complex consisting of a receptor, an adaptor protein, and procaspase-1 that induces the secretion of the mature form of IL-1β in response to microbial infection and danger signals. Activation of the NLRP3 inflammasome induced by endogenous danger signal molecules is closely linked to the development and progress of chronic inflammatory diseases. The oxidation of phospholipids occurs upon cellular stress and damage, resulting in the accumulation of oxidized phosphatidylcholines (oxPAPC) such as 1-palmitoyl-2-(5-oxovaleroyl)-sn-glycero-phosphocholine (POVPC) at inflammatory sites. In this study, we investigated whether oxidized phosphatidylcholine induces the activation of NLRP3 inflammasome in macrophages, leading to the secretion of IL-1β. POVPC induced the degradation of procaspase-1 to caspase-1(p10), the cleavage of pro-IL-1β to IL-1β, and oligomerization of ASC in primary mouse bone marrow-derived macrophages. POVPC-induced production of caspase-1, and IL-1β was abolished in macrophages derived from NLRP3- or caspase-1-deficient mice. In an air pouch model and a peritonitis model in mice, POVPC injection resulted in the production of caspase-1(p10), IL-1β, and IL-18 in wild-type, but not in NLRP3-deficient, mice. POVPC-induced inflammasome activation was mediated by mitochondrial reactive oxygen species resulting from intracellular Ca2+ signaling and mitochondrial destabilization. Our results demonstrate that endogenously produced oxidized phosphatidylcholines such as POVPC induce the activation of NLRP3 inflammasome, leading to the production of IL-1β in macrophages. The results provide an insight to understand how the oxidized lipids endogenously produced upon cellular stress and tissue damage contribute to the inflammatory reaction at pathologic sites.
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