Center of Allergy and Environment (ZAUM), Technical University of Munich and Helmholtz Center Munich, 80802 Munich, Germany.
Faculty of Biology and Medicine, University of Lausanne, Service de Pneumologie, Centre Hospitalier Universitaire Vaudois, 1066 Epalinges, Switzerland.
Sci Transl Med. 2020 Apr 22;12(540). doi: 10.1126/scitranslmed.aay0605.
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 (), 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 -driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E (PGE) and IL-10] and suppressed chemotaxis. also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with extract attenuated allergic airway inflammation in mice, and intranasal transfer of -conditioned macrophages led to reduced airway eosinophilia in a COX/PGE-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in GDH activity was required for anti-inflammatory effects of in macrophages, and local administration of recombinant 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.
类二十烷酸是 2 型炎症的关键介质，例如在过敏和哮喘中。寄生虫产品已被提议作为治疗炎症性疾病的方法，但它们对类二十烷酸的影响尚不清楚。在这里，我们表明，已知调节 2 型反应的寄生虫幼虫产物通过抑制 5-脂氧合酶途径但诱导环氧化酶 (COX) 途径触发广泛的抗炎类二十烷酸转移。在人类巨噬细胞和粒细胞中，-驱动的 COX 途径的诱导导致抗炎介质的产生（例如前列腺素 E (PGE) 和 IL-10）和趋化作用的抑制。 还消除了患有阿司匹林加重性呼吸道疾病 (AERD) 的患者粒细胞的趋化作用，AERD 是一种严重的 2 型炎症状态。用 提取物进行鼻内治疗可减轻小鼠的过敏性气道炎症，并且 -调理的巨噬细胞的鼻内转移以 COX/PGE 依赖的方式导致气道嗜酸性粒细胞减少。巨噬细胞中调节介质的诱导取决于 p38 有丝分裂原激活蛋白激酶 (MAPK)、缺氧诱导因子-1α (HIF-1α) 和谷氨酸脱氢酶 (GDH)，我们将其鉴定为 中的主要免疫调节蛋白。GDH 活性对于 对巨噬细胞的抗炎作用是必需的，并且将重组 GDH 局部施用到气道中可消除小鼠的过敏性气道炎症。因此，寄生虫幼虫中存在的代谢酶可以通过诱导抗炎类二十烷酸转换来抑制 2 型炎症，这对过敏和哮喘的治疗具有重要意义。
