Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.
Autoimmune disease-associated variants of extracellular endoplasmic reticulum aminopeptidase 1 induce altered innate immune responses by human immune cells.
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DOI：
10.1159/000368899
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发表时间：
2015
影响因子：
5.3
通讯作者：
Amalfitano A
中科院分区：
文献类型：
--
作者：
Aldhamen YA;Pepelyayeva Y;Rastall DP;Seregin SS;Zervoudi E;Koumantou D;Aylsworth CF;Quiroga D;Godbehere S;Georgiadis D;Stratikos E;Amalfitano A
ERAP1基因多态性与几种自身免疫性疾病有关；然而，这些关联背后的分子机制尚不清楚。最近，我们已经证明ERAP1调节先天免疫反应的关键方面。此外，先前的研究表明ERAP1定位于er，并在炎症期间分泌。在此，我们研究了ERAP1多态性变异在调节人类PBMCs先天免疫应答中可能发挥的作用，采用两种实验方法：细胞外暴露于ERAP1变异和基于腺病毒的ERAP1表达。我们发现，hpbmc暴露于ERAP1变异蛋白以及Ad载体过度表达ERAP1增加了炎症细胞因子和趋化因子的产生，并增强了免疫细胞的激活。研究这些反应背后的分子机制表明，ERAP1能够通过多种途径激活先天免疫，包括NLRP3炎性体。重要的是，如果在检测系统中检测ERAP1的自身免疫性疾病相关变异，这些反应就会发生变化。出乎意料的是，阻断ERAP1细胞内化增加了IL-1β的产生。据我们所知，这是首次发现ERAP1参与调节人类免疫细胞的先天反应，这一发现可能解释了为什么ERAP1与几种自身免疫性疾病存在遗传关联。
ERAP1 gene polymorphisms have been linked to several autoimmune diseases; however, the molecular mechanisms underlying these associations are not well understood. Recently, we have demonstrated that ERAP1 regulates key aspects of the innate immune response. Moreover, previous studies show ERAP1 to be ER-localized and secreted during inflammation. Herein, we investigate the possible roles that ERAP1 polymorphic variants may have in modulating innate immune responses of human PBMCs using two experimental methods: extracellular exposure of hPBMCs to ERAP1 variants and adenovirus-based ERAP1 expression. We found that exposure of hPBMCs to ERAP1 variant proteins as well as ERAP1 overexpression by Ad vectors increased inflammatory cytokine and chemokine production, and enhanced immune cell activation. Investigating the molecular mechanisms behind these responses revealed that ERAP1 is able to activate innate immunity via multiple pathways, including the NLRP3 inflammasome. Importantly, these responses varied if autoimmune-disease-associated variants of ERAP1 were examined in the assay systems. Unexpectedly, blocking ERAP1 cellular internalization augmented IL-1β production. To our knowledge, this is the first report identifying ERAP1 as being involved in modulating innate responses of human immune cells, a finding that may explain why ERAP1 has been genetically associated with several autoimmune diseases.
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影响因子：
64.5
作者：
Kastner DL;Aksentijevich I;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
16
作者：
Martinon, F;Burns, K;Tschopp, J
通讯作者：
Tschopp, J
影响因子：
30.5
作者：
Baroja-Mazo, Alberto;Martin-Sanchez, Fatima;Pelegrin, Pablo
通讯作者：
Pelegrin, Pablo
影响因子：
2.7
作者：
Amstad, PA;Yu, G;Phelps, DJ
通讯作者：
Phelps, DJ
影响因子：
3.5
作者：
Goto, Y;Hattori, A;Tsujimoto, M
通讯作者：
Tsujimoto, M