Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases
Myeloperoxidase Modulates Inflammation in Generalized Pustular Psoriasis and Additional Rare Pustular Skin Diseases
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DOI：
10.1016/j.ajhg.2020.07.001
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发表时间：
2020-09-03
影响因子：
9.8
通讯作者：
Hueffmeier, Ulrike
中科院分区：
文献类型：
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作者：
Haskamp, Stefan;Bruns, Heiko;Hueffmeier, Ulrike
全身性脓疱性银屑病 (GPP) 是一种严重的多系统炎症性疾病，以中性粒细胞性脓疱病为特征，由皮肤中促炎性 IL-36 细胞因子引发。虽然 19%-41% 的受影响个体存在 IL36RN 双等位基因突变，但大多数情况下遗传原因尚不清楚。为了识别和表征 GPP 发病机制中涉及的新途径，我们对 31 名 GPP 患者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。我们发现了八种 MPO 突变，导致中性粒细胞和单核细胞缺乏 MPO。 MPO 突变，主要是导致 MPO 完全缺乏的突变，与 GPP 累积相关（p = 1.85E-08；OR = 6.47）。 82 名受影响个体和超过 4,900 名对照受试者之间的突变 MPO 等位基因数量存在显着差异 (p = 1.04E-09)；当包括 IL36RN 突变 (1.48E-13) 时，这种效应更强，并且与发病年龄较小相关 (p = 0.0018)。四种蛋白酶的活性（之前被认为是 IL-36 前体的激活酶）与 MPO 缺乏相关。在受影响的细胞中，佛波醇-肉豆蔻酸酯-乙酸酯诱导的中性粒细胞胞外陷阱 (NET) 的形成减少 (p = 0.015)，并且 MPO 缺陷小鼠和人类细胞中的吞噬作用测定显示，中性粒细胞功能改变，单核细胞对中性粒细胞的清除受损（胞吞作用），从而使中性粒细胞在细胞中持续存在时间延长。 发炎的皮肤。 MPO 突变对 GPP 的发病机制有显着影响。我们认为 MPO 作为人类的炎症调节剂，可调节蛋白酶活性和 NET 形成并改变胞吞作用。我们的研究结果表明 MPO 抑制剂在心血管疾病中的应用可能具有重要意义。 MPO 和受影响的通路是诱导中性粒细胞介导的皮肤病炎症消退的有吸引力的靶点。
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.