An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products
An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products
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DOI：
10.1126/scitranslmed.aay0605
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发表时间：
2020-04-22
影响因子：
17.1
通讯作者：
Esser-von Bieren, Julia
中科院分区：
文献类型：
--
作者：
Jimenez, Marta de los Reyes;Lechner, Antonie;Esser-von Bieren, Julia
类二十烷酸是2型炎症的关键介质，例如，过敏症和哮喘蠕虫产品已被建议作为治疗炎症性疾病的药物，但它们对类花生酸的影响尚不清楚。在这里，我们表明，蠕虫Heligmosomoides polygyrus bakeri（HPBE），已知调节2型反应的幼虫产品，触发广泛的抗炎类花生酸转变抑制5-脂氧合酶途径，但诱导环氧合酶（考克斯）途径。在人巨噬细胞和粒细胞中，HpbE驱动的考克斯途径的诱导导致抗炎介质的产生[例如，前列腺素E-2（PGE（2））和IL-10]并抑制趋化性。HpbE还消除了阿司匹林加重的呼吸道疾病（AERD）（一种严重的2型炎性疾病）患者的粒细胞趋化性。HpbE提取物鼻内治疗可减轻小鼠的过敏性气道炎症，HpbE条件巨噬细胞的鼻内转移可导致气道嗜酸性粒细胞以考克斯/PGE（2）依赖性方式减少。巨噬细胞中调节介质的诱导依赖于p38丝裂原活化蛋白激酶（MAPK）、缺氧诱导因子-1 α（HIF-1 α）和Hpb谷氨酸脱氢酶（GDH），我们将其确定为HpbE中的主要免疫调节蛋白。Hpb GDH活性是HpbE在巨噬细胞中的抗炎作用所必需的，并且将重组Hpb GDH局部施用至气道消除了小鼠的过敏性气道炎症。因此，蠕虫幼虫中存在的代谢酶可以通过诱导抗炎类花生酸转换来抑制2型炎症，这对过敏和哮喘的治疗具有重要意义。
Eicosanoids are key mediators of type-2 inflammation, e.g., in allergy and asthma. Helminth products have been suggested as remedies against inflammatory diseases, but their effects on eicosanoids are unknown. Here, we show that larval products of the helminth Heligmosomoides polygyrus bakeri (HpbE), known to modulate type-2 responses, trigger a broad anti-inflammatory eicosanoid shift by suppressing the 5-lipoxygenase pathway, but inducing the cyclooxygenase (COX) pathway. In human macrophages and granulocytes, the HpbE-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E-2 (PGE(2)) and IL-10] and suppressed chemotaxis. HpbE also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with HpbE extract attenuated allergic airway inflammation in mice, and intranasal transfer of HpbE-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE(2)-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1 alpha (HIF-1 alpha), and Hpb glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in HpbE. Hpb GDH activity was required for anti-inflammatory effects of HpbE in macrophages, and local administration of recombinant Hpb GDH to the airways abrogated allergic airway inflammation in mice. Thus, a metabolic enzyme present in helminth larvae can suppress type-2 inflammation by inducing an anti-inflammatory eicosanoid switch, which has important implications for the therapy of allergy and asthma.