Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.
Endoplasmic reticulum aminopeptidase-1 functions regulate key aspects of the innate immune response.
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DOI：
10.1371/journal.pone.0069539
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Amalfitano A
中科院分区：
文献类型：
--
作者：
Aldhamen YA;Seregin SS;Rastall DP;Aylsworth CF;Pepelyayeva Y;Busuito CJ;Godbehere-Roosa S;Kim S;Amalfitano A
内质网氨基肽酶-1(ERAP1)是一种多功能的、普遍表达的酶，其在MHC I类分子呈递的抗原加工过程中的修剪作用已为人们所熟知，然而，ERAP1在调节全球先天免疫反应中的作用迄今尚未被阐明。在这里，我们证明，与野生型小鼠相比，缺乏ERAP1的小鼠在病原体识别的早期表现出过度的先天免疫反应，其特征是脾和肝脏的NK和NKT细胞激活增加，以及促炎细胞因子的产生增加，如IL12和MCP1。我们的数据还显示，ERAP1在NK细胞的发育和功能中发挥着关键作用。我们观察到ERAP1-KO小鼠终末成熟NK细胞的频率更高，以及获得许可的NK细胞(表达Ly49C和Ly49I受体)的频率更高，这一结果与ERAP1-KO小鼠在促炎刺激下增强的NK活性和干扰素γ的产生呈正相关。此外，在病原体识别过程中，ERAP1特异性地调节CD11c+DC产生IL12，IL12产生的增加与脾DC和巨噬细胞吞噬活性的增强呈正相关。综上所述，我们的结果表明，ERAP1蛋白在调节先天性免疫系统发育的几个方面及其在病原体识别的初始阶段的反应中发挥了以前未被认识到的更核心的作用。这种作用可能解释了为什么ERAP1被GWAs牵连到自身免疫性疾病的发病机制中，这些疾病可能是由对病原体遭遇的异常反应引起的。
Endoplasmic reticulum aminopeptidase-1 (ERAP1) is a multifunctional, ubiquitously expressed enzyme whose peptide-trimming role during antigen processing for presentation by MHC I molecules is well established, however, a role for ERAP1 in modulating global innate immune responses has not been described to date. Here we demonstrate that, relative to wild type mice, mice lacking ERAP1 exhibit exaggerated innate immune responses early during pathogen recognition, as characterized by increased activation of splenic and hepatic NK and NKT cells and enhanced production of pro-inflammatory cytokines such as IL12 and MCP1. Our data also revealed that ERAP1 is playing a critical role in NK cell development and function. We observed higher frequencies of terminally matured NK cells, as well as higher frequencies of licensed NK cells (expressing the Ly49C and Ly49I receptors) in ERAP1-KO mice, results that positively correlated with an enhanced NK activation and IFNγ production by ERAP1-KO mice challenged with pro-inflammatory stimuli. Furthermore, during pathogen recognition, ERAP1 regulates IL12 production by CD11c+ DCs specifically, with increases in IL12 production positively correlated with an increased phagocytic activity of splenic DCs and macrophages. Collectively, our results demonstrate a previously unrecognized, more central role for the ERAP1 protein in modulating several aspects of both the development of the innate immune system, and its responses during the initial stages of pathogen recognition. Such a role may explain why ERAP1 has been implicated by GWAS in the pathogenesis of autoimmune diseases that may be precipitated by aberrant responses to pathogen encounters.
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影响因子：
5.1
作者：
Appledorn, D. M.;Kiang, A.;Amalfitano, A.
通讯作者：
Amalfitano, A.
影响因子：
4.4
作者：
Aldhamen, Yasser Ali;Seregin, Sergey S.;Amalfitano, Andrea
通讯作者：
Amalfitano, Andrea
影响因子：
3.7
作者：
Guerini FR;Cagliani R;Forni D;Agliardi C;Caputo D;Cassinotti A;Galimberti D;Fenoglio C;Biasin M;Asselta R;Scarpini E;Comi GP;Bresolin N;Clerici M;Sironi M
通讯作者：
Sironi M
内质网氨基肽酶在健康和疾病中的作用：从感染到癌症。
影响因子：
5.6
作者：
Cifaldi L;Romania P;Lorenzi S;Locatelli F;Fruci D
通讯作者：
Fruci D
影响因子：
3.7
作者：
Evnouchidou I;Momburg F;Papakyriakou A;Chroni A;Leondiadis L;Chang SC;Goldberg AL;Stratikos E
通讯作者：
Stratikos E