An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products

• Published in: Science translational medicine 2020-04, Vol.12 (540), p.1
• Main Authors: de Los Reyes Jiménez, Marta, Lechner, Antonie, Alessandrini, Francesca, Bohnacker, Sina, Schindela, Sonja, Trompette, Aurélien, Haimerl, Pascal, Thomas, Dominique, Henkel, Fiona, Mourão, André, Geerlof, Arie, da Costa, Clarissa Prazeres, Chaker, Adam M, Brüne, Bernhard, Nüsing, Rolf, Jakobsson, Per-Johan, Nockher, Wolfgang A, Feige, Matthias J, Haslbeck, Martin, Ohnmacht, Caspar, Marsland, Benjamin J, Voehringer, David, Harris, Nicola L, Schmidt-Weber, Carsten B, Esser-von Bieren, Julia
• Format: Article
• Language: English
• Subjects: Allergies; Arachidonate 5-lipoxygenase; Aspirin; Asthma; Chemotaxis; Eicosanoids; Eosinophilia; Glutamate dehydrogenase; Hypoxia-inducible factor 1a; Immunoregulation; Inflammatory diseases; Interleukin 10; Leukocytes (granulocytic); Lipoxygenase; Macrophages; MAP kinase; Medicin och hälsovetenskap; Prostaglandin E2; Prostaglandin endoperoxide synthase; Protein kinase; Respiratory diseases; Respiratory tract; Respiratory tract diseases
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• 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.