Nematode ascarosides attenuate mammalian type 2 inflammatory responses.
Nematode ascarosides attenuate mammalian type 2 inflammatory responses.
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DOI：
10.1073/pnas.2108686119
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发表时间：
2022-03-01
影响因子：
11.1
通讯作者：
Nakayama T
中科院分区：
文献类型：
--
作者：
Shinoda K;Choe A;Hirahara K;Kiuchi M;Kokubo K;Ichikawa T;Hoki JS;Suzuki AS;Bose N;Appleton JA;Aroian RV;Schroeder FC;Sternberg PW;Nakayama T
动物概念验证研究表明，蛔虫对免疫失调性疾病具有保护作用，但如果没有单独的线虫衍生分子进行开发和测试，则很难在人体试验中进行研究。我们发现蛔苷（多种线虫分泌的分子）除了可以减少记忆型致病性 Th2 细胞和 ILC2 并增加肺中表达 Il10 的间质巨噬细胞亚群外，还可以通过调节 Il33（诱导 2 型免疫的关键上皮细胞因子）的表达来抑制啮齿动物模型中的哮喘。因此，蛔苷通过影响先天性和适应性免疫来抑制 2 型免疫反应，并可能定义一类有效的小分子药物来治疗过敏性气道疾病。越来越多的证据表明，线虫感染可以预防免疫失调疾病。活体寄生虫或其排泄/分泌 (ES) 产品的施用已在多种动物模型中显示出对包括哮喘在内的免疫疾病的治疗效果。摄入活寄生虫治疗免疫疾病的人体临床试验已经产生了有希望的结果，但对病原生物的摄入和蛋白质成分的免疫原性的担忧仍然存在。尽管为确定 ES 产品的活性成分做出了广泛的努力，但尚未从线虫中鉴定出具有免疫调节活性的小分子。在这里，我们证明了一种进化上保守的线虫信息素家族，称为蛔苷，可以强烈调节小鼠的肺部免疫反应并降低哮喘严重程度。在卵清蛋白 (OVA) 小鼠模型中筛选动物寄生线虫产生的蛔苷对哮喘发展的抑制作用，我们发现施用纳克量的 ascr#7 可预防肺嗜酸性粒细胞增多、杯状细胞化生和气道高反应性的发展。 Ascr#7 抑制肺上皮细胞产生 IL-33，并减少肺中记忆型致病性 Th2 细胞和 ILC2 的数量，这两者都是哮喘病理的关键驱动因素。我们的研究结果表明，哺乳动物免疫系统将蛔苷视为寄生线虫进化上保守的分子特征。鉴定出线虫产生的小分子，该小分子是 ES 产品有据可查的免疫调节作用的基础，可能有助于开发过敏性疾病的治疗策略。
Animal proof-of-concept studies have shown that roundworms have a protective effect against immune-dysregulated disorders, but it has been difficult to study in human trials without individual nematode-derived molecules to develop and test. We discovered that ascarosides, molecules that are secreted by diverse nematodes, suppress asthma in a rodent model via modulation of expression of Il33, a key epithelial cytokine for induction of type 2 immunity, in addition to decreasing memory-type pathogenic Th2 cells and ILC2s and increasing the Il10-expressing subpopulation of interstitial macrophages in the lung. Thus, ascarosides suppress type 2 immune response by affecting both innate and adaptive immunity and could define a potent class of small molecule drugs to treat allergic airway diseases. Mounting evidence suggests that nematode infection can protect against disorders of immune dysregulation. Administration of live parasites or their excretory/secretory (ES) products has shown therapeutic effects across a wide range of animal models for immune disorders, including asthma. Human clinical trials of live parasite ingestion for the treatment of immune disorders have produced promising results, yet concerns persist regarding the ingestion of pathogenic organisms and the immunogenicity of protein components. Despite extensive efforts to define the active components of ES products, no small molecules with immune regulatory activity have been identified from nematodes. Here we show that an evolutionarily conserved family of nematode pheromones called ascarosides strongly modulates the pulmonary immune response and reduces asthma severity in mice. Screening the inhibitory effects of ascarosides produced by animal-parasitic nematodes on the development of asthma in an ovalbumin (OVA) murine model, we found that administration of nanogram quantities of ascr#7 prevented the development of lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Ascr#7 suppressed the production of IL-33 from lung epithelial cells and reduced the number of memory-type pathogenic Th2 cells and ILC2s in the lung, both key drivers of the pathology of asthma. Our findings suggest that the mammalian immune system recognizes ascarosides as an evolutionarily conserved molecular signature of parasitic nematodes. The identification of a nematode-produced small molecule underlying the well-documented immunomodulatory effects of ES products may enable the development of treatment strategies for allergic diseases.
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影响因子：
3.8
作者：
Hotez PJ;Alvarado M;Basáñez MG;Bolliger I;Bourne R;Boussinesq M;Brooker SJ;Brown AS;Buckle G;Budke CM;Carabin H;Coffeng LE;Fèvre EM;Fürst T;Halasa YA;Jasrasaria R;Johns NE;Keiser J;King CH;Lozano R;Murdoch ME;O'Hanlon S;Pion SD;Pullan RL;Ramaiah KD;Roberts T;Shepard DS;Smith JL;Stolk WA;Undurraga EA;Utzinger J;Wang M;Murray CJ;Naghavi M
通讯作者：
Naghavi M
影响因子：
9.2
作者：
Choe, Andrea;von Reuss, Stephan H.;Kogan, Dima;Gasser, Robin B.;Platzer, Edward G.;Schroeder, Frank C.;Sternberg, Paul W.
通讯作者：
Sternberg, Paul W.
影响因子：
29.7
作者：
Kanno Y;Vahedi G;Hirahara K;Singleton K;O'Shea JJ
通讯作者：
O'Shea JJ
影响因子：
9.2
作者：
Hsueh, Yen-Ping;Mahanti, Parag;Schroeder, Frank C.;Sternberg, Paul W.
通讯作者：
Sternberg, Paul W.
影响因子：
32.4
作者：
Hondowicz BD;An D;Schenkel JM;Kim KS;Steach HR;Krishnamurty AT;Keitany GJ;Garza EN;Fraser KA;Moon JJ;Altemeier WA;Masopust D;Pepper M
通讯作者：
Pepper M