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Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases.
American Journal of Human Genetics ( IF 8.1 ) Pub Date : 2020-08-05 , DOI: 10.1016/j.ajhg.2020.07.001
Stefan Haskamp 1 , Heiko Bruns 2 , Madelaine Hahn 3 , Markus Hoffmann 3 , Anne Gregor 1 , Sabine Löhr 1 , Jonas Hahn 3 , Christine Schauer 3 , Mark Ringer 3 , Cindy Flamann 2 , Benjamin Frey 4 , Adam Lesner 5 , Christian T Thiel 1 , Arif B Ekici 1 , Stephan von Hörsten 6 , Gunter Aßmann 7 , Claudia Riepe 8 , Maximilien Euler 3 , Knut Schäkel 9 , Sandra Philipp 10 , Jörg C Prinz 11 , Rotraut Mößner 12 , Florina Kersting 13 , Michael Sticherling 13 , Abdelaziz Sefiani 14 , Jaber Lyahyai 14 , Wiebke Sondermann 15 , Vinzenz Oji 8 , Peter Schulz 16 , Dagmar Wilsmann-Theis 17 , Heinrich Sticht 18 , Georg Schett 3 , André Reis 1 , Steffen Uebe 1 , Silke Frey 3 , Ulrike Hüffmeier 1
Affiliation  

Generalized pustular psoriasis (GPP) is a severe multi-systemic inflammatory disease characterized by neutrophilic pustulosis and triggered by pro-inflammatory IL-36 cytokines in skin. While 19%–41% of affected individuals harbor bi-allelic mutations in IL36RN, the genetic cause is not known in most cases. To identify and characterize new pathways involved in the pathogenesis of GPP, we performed whole-exome sequencing in 31 individuals with GPP and demonstrated effects of mutations in MPO encoding the neutrophilic enzyme myeloperoxidase (MPO). We discovered eight MPO mutations resulting in MPO -deficiency in neutrophils and monocytes. MPO mutations, primarily those resulting in complete MPO deficiency, cumulatively associated with GPP (p = 1.85E−08; OR = 6.47). The number of mutant MPO alleles significantly differed between 82 affected individuals and >4,900 control subjects (p = 1.04E−09); this effect was stronger when including IL36RN mutations (1.48E−13) and correlated with a younger age of onset (p = 0.0018). The activity of four proteases, previously implicated as activating enzymes of IL-36 precursors, correlated with MPO deficiency. Phorbol-myristate-acetate-induced formation of neutrophil extracellular traps (NETs) was reduced in affected cells (p = 0.015), and phagocytosis assays in MPO-deficient mice and human cells revealed altered neutrophil function and impaired clearance of neutrophils by monocytes (efferocytosis) allowing prolonged neutrophil persistence in inflammatory skin. MPO mutations contribute significantly to GPP’s pathogenesis. We implicate MPO as an inflammatory modulator in humans that regulates protease activity and NET formation and modifies efferocytosis. Our findings indicate possible implications for the application of MPO inhibitors in cardiovascular diseases. MPO and affected pathways represent attractive targets for inducing resolution of inflammation in neutrophil-mediated skin diseases.



中文翻译:

髓过氧化物酶调节全身性脓疱型银屑病和其他罕见的脓疱性皮肤病的炎症。

广义脓疱性牛皮癣(GPP)是一种严重的多系统性炎症性疾病,其特征在于嗜中性脓疱病并由皮肤中促炎性IL-36细胞因子触发。尽管有19%–41%的受影响个体在IL36RN中具有双等位基因突变,但在大多数情况下其遗传原因尚不清楚。为了鉴定和表征参与GPP发病机制的新途径,我们在31名GPP个体中进行了全外显子组测序,并证明了编码中性粒细胞髓过氧化物酶(MPO)的MPO突变的影响。我们发现了8个MPO突变,导致嗜中性粒细胞和单核细胞缺乏MPO。MPO突变,主要是那些导致MPO完全缺失的突变,与GPP累积相关(p = 1.85E-08; OR = 6.47)。突变的MPO等位基因的数目在82个受影响个体和> 4,900个对照受试者之间有显着差异(p = 1.04E-09);当包含IL36RN时,这种作用更强突变(1.48E-13)并与较年轻的发病年龄相关(p = 0.0018)。先前与IL-36前体的活化酶有关的四种蛋白酶的活性与MPO缺乏有关。在受影响的细胞中,肉豆蔻酸乙酸乙酸酯诱导的嗜中性粒细胞胞外陷阱(NETs)形成减少(p = 0.015),MPO缺陷小鼠和人类细胞中的吞噬作用分析显示嗜中性粒细胞功能改变,单核细胞清除嗜中性粒细胞(排尿)可使中性粒细胞在炎症性皮肤中持续存在。MPO突变显着促进了GPP的发病机理。我们暗示MPO作为人类的炎症调节剂,可调节蛋白酶的活性和NET的形成,并修饰胞吞作用。我们的发现表明,MPO抑制剂在心血管疾病中的应用可能具有潜在意义。MPO和受影响的途径代表诱使中性粒细胞介导的皮肤疾病炎症消退的靶标。

更新日期:2020-09-03
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