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

Abstract

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 <i>Heligmosomoides polygyrus bakeri</i> (<i>HpbE</i>), 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 <i>HpbE</i>-driven induction of the COX pathway resulted in the production of anti-inflammatory mediators [e.g., prostaglandin E₂ (PGE₂) and IL-10] and suppressed chemotaxis. <i>HpbE</i> also abrogated the chemotaxis of granulocytes from patients suffering from aspirin-exacerbated respiratory disease (AERD), a severe type-2 inflammatory condition. Intranasal treatment with <i>HpbE</i> extract attenuated allergic airway inflammation in mice, and intranasal transfer of <i>HpbE</i>-conditioned macrophages led to reduced airway eosinophilia in a COX/PGE₂-dependent fashion. The induction of regulatory mediators in macrophages depended on p38 mitogen-activated protein kinase (MAPK), hypoxia-inducible factor-1α (HIF-1α), and <i>Hpb</i> glutamate dehydrogenase (GDH), which we identify as a major immunoregulatory protein in <i>HpbE</i> <i>Hpb</i> GDH activity was required for anti-inflammatory effects of <i>HpbE</i> in macrophages, and local administration of recombinant <i>Hpb</i> 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.