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Therapeutic ACPA inhibits NET formation: a potential therapy for neutrophil-mediated inflammatory diseases
Cellular & Molecular Immunology ( IF 21.8 ) Pub Date : 2020-03-20 , DOI: 10.1038/s41423-020-0381-3
Renato G S Chirivi 1, 2 , Jos W G van Rosmalen 1 , Maarten van der Linden 1, 2 , Maximilien Euler 3 , Gonny Schmets 1 , Galina Bogatkevich 4 , Konstantinos Kambas 5 , Jonas Hahn 3 , Quinte Braster 6 , Oliver Soehnlein 6, 7, 8 , Markus H Hoffmann 3 , Helmuth H G van Es 2 , Jos M H Raats 1
Affiliation  

Excessive release of neutrophil extracellular traps (NETs) is associated with disease severity and contributes to tissue injury, followed by severe organ damage. Pharmacological or genetic inhibition of NET release reduces pathology in multiple inflammatory disease models, indicating that NETs are potential therapeutic targets. Here, we demonstrate using a preclinical basket approach that our therapeutic anti-citrullinated protein antibody (tACPA) has broad therapeutic potential. Treatment with tACPA prevents disease symptoms in various mouse models with plausible NET-mediated pathology, including inflammatory arthritis (IA), pulmonary fibrosis, inflammatory bowel disease and sepsis. We show that citrulline residues in the N-termini of histones 2A and 4 are specific targets for therapeutic intervention, whereas antibodies against other N-terminal post-translational histone modifications have no therapeutic effects. Because citrullinated histones are generated during NET release, we investigated the ability of tACPA to inhibit NET formation. tACPA suppressed NET release from human neutrophils triggered with physiologically relevant human disease-related stimuli. Moreover, tACPA diminished NET release and potentially initiated NET uptake by macrophages in vivo, which was associated with reduced tissue damage in the joints of a chronic arthritis mouse model of IA. To our knowledge, we are the first to describe an antibody with NET-inhibiting properties and thereby propose tACPA as a drug candidate for NET-mediated inflammatory diseases, as it eliminates the noxious triggers that lead to continued inflammation and tissue damage in a multidimensional manner.



中文翻译:

治疗性 ACPA 抑制 NET 形成:中性粒细胞介导的炎症性疾病的潜在疗法

中性粒细胞胞外陷阱(NET)的过度释放与疾病的严重程度相关,并导致组织损伤,进而导致严重的器官损伤。NET 释放的药理学或遗传抑制可减少多种炎症性疾病模型的病理学,表明 NET 是潜在的治疗靶点。在这里,我们使用临床前篮子方法证明我们的治疗性抗瓜氨酸蛋白抗体(tACPA)具有广泛的治疗潜力。tACPA 治疗可预防各种具有 NET 介导病理学的小鼠模型的疾病症状,包括炎症性关节炎 (IA)、肺纤维化、炎症性肠病和败血症。我们发现组蛋白 2A 和 4 N 末端的瓜氨酸残基是治疗干预的特定靶点,而针对其他 N 末端翻译后组蛋白修饰的抗体则没有治疗作用。由于瓜氨酸组蛋白是在 NET 释放过程中产生的,因此我们研究了 tACPA 抑制 NET 形成的能力。tACPA 抑制由生理相关的人类疾病相关刺激触发的人类中性粒细胞的 NET 释放。此外,tACPA 减少了 NET 的释放,并可能引发体内巨噬细胞对 NET 的摄取,这与 IA 慢性关节炎小鼠模型关节组织损伤的减少有关。据我们所知,我们是第一个描述具有 NET 抑制特性的抗体,从而提出 tACPA 作为 NET 介导的炎症性疾病的候选药物,因为它以多维方式消除了导致持续炎症和组织损伤的有害触发因素。

更新日期:2020-04-24
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