Circulating Peroxiredoxin-1 is a novel damage-associated molecular pattern and aggravates acute liver injury via promoting inflammation
Circulating Peroxiredoxin-1 is a novel damage-associated molecular pattern and aggravates acute liver injury via promoting inflammation
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循环中的 Peroxiredoxin-1 是一种新的损伤相关分子模式，可通过促进炎症加重急性肝损伤
DOI：
10.1016/j.freeradbiomed.2019.04.012
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发表时间：
2019-06-01
影响因子：
7.4
通讯作者：
Yang, Huixiang
中科院分区：
文献类型：
--
作者：
He, Ying;Li, Shenglan;Yang, Huixiang
无菌炎症是由损伤相关的分子模式(DAMP)引发的，是急性肝损伤(ALI)的关键因素。然而，目前对ALI下激活肝脏炎症的那些阻滞剂的了解仍然不完整。我们在此报道循环中的过氧化还蛋白-1(Prdx1)是一种治疗ALI的新型阻滞剂。小鼠腹腔注射对乙酰氨基酚(APAP)后12~24 h出现进行性ALI，并伴有明显的肝脏炎症，表现为巨噬细胞浸润和细胞因子(IL-1β、IL-6和TNF-α)的上调；这些变化与血清Prdx1的强健和进行性产生同时发生。在四氯化碳(CCl4)诱导的小鼠ALI中也得到了类似的观察。去除血清Prdx1来源可保护Prdx1缺陷小鼠免受APAP和CCl4诱导的肝损伤，并减少巨噬细胞浸润、IL-1β、IL-6和TNF-α的产生。结果，Prdx1(-/-)小鼠在APAP诱导的死亡中得到了强有力的保护，这种死亡可能是ALI的进展。此外，在Prdx1(-/-)小鼠体内再次静脉注射重组Prdx1(RPrdx1)逆转或减少了上述所有事件，证明了循环Prdx1对ALI的重要贡献。RPrdx1通过核因子-kappaB信号和Nod样受体家族3(NLRP3)炎症体信号，有效地诱导原代巨噬细胞表达前IL-1β、IL-6、TNF-α和IL-1β，明显表现为caspase-1激活。此外，ALI患者(n=15)血清Prdx1水平显著升高，这种升高与ALI的严重程度相关。总而言之，我们提供了血清Prdx1在ALI中的作用的第一个证据。
Sterile inflammation is initiated by damage-associated molecular patterns (DAMPs) and a key contributor to acute liver injury (ALI). However, the current knowledge on those DAMPs that activate hepatic inflammation under ALI remains incomplete. We report here that circulating peroxiredoxin-1 (Prdx1) is a novel DAMP for ALI. Intraperitoneal injection of acetaminophen (APAP) elicited a progressive course of ALI in mice, which was developed from 12 to 24 h post injection along with liver inflammation evident by macrophage infiltration and upregulations of cytokines (IL-1 beta,IL-6 and TNF-alpha); these alterations were concurrently occurred with a robust and progressive production of serum Prdx1. Similar observations were also obtained in carbon tetrachloride (CCl4)-induced ALI in mice. Removal of the source of serum Prdx1 protected mice deficient in Prdx1 from APAP and CCl4-induced liver injury, and decreased macrophage infiltration, IL-1 beta, IL-6 and TNF-alpha production. As a result, Prdx1(-/-) mice were strongly protected from APAP-induced death that was likely progressed from ALI. Additionally, intravenous re-introduction of recombinant Prdx1 (rPrdx1) in Prdx1(-/-) mice reversed or reduced all the above events, demonstrating an important contribution of circulating Prdx1 to ALI. rPrdx1 potently induced in primary macrophages the expression of pro-IL-1 beta, IL-6, TNF-alpha, and IL-1 beta through the NF-kappa B signaling as well as the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome signaling, evident by caspase-1 activation. Furthermore, a significant elevation of serum Prdx1 was demonstrated in patients (n = 15) with ALI; the elevation is associated with ALI severity. Collectively, we provide the first demonstration for serum Prdx1 contributing to ALI.