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 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 E2 (PGE2) 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/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 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.

What Can Parasites Tell Us About the Pathogenesis and Treatment of Asthma and Allergic Diseases

“…Finally, HpbE reduced the chemotaxis of granulocytes from patients suffering from type 2 airway inflammation (16).…”

“…The H. polygyrus larval extract (HpbE) and its active protein component, Hpb GDH, efficiently suppressed HDM-induced AAI in vivo. In particular, HpbE and recombinant Hpb GDH modulated the arachidonic acid metabolism of macrophages, inducing an anti-inflammatory, type 2 suppressive eicosanoid profile (16). HpbE-/GDH-treated macrophages exhibited high IL-10 and prostaglandin E 2 (PGE 2 ) production, but low production of proinflammatory leukotrienes, which are key mediators of AAI (16,108).…”

“…In particular, HpbE and recombinant Hpb GDH modulated the arachidonic acid metabolism of macrophages, inducing an anti-inflammatory, type 2 suppressive eicosanoid profile (16). HpbE-/GDH-treated macrophages exhibited high IL-10 and prostaglandin E 2 (PGE 2 ) production, but low production of proinflammatory leukotrienes, which are key mediators of AAI (16,108). Macrophage-derived PGE 2 was particularly important for the HpbE-driven regulation of AAI in this study, and another study found that also helminths themselves can produce this immunomodulatory mediator (109).…”

“…Epidemiological evidence on the reciprocity between helminthiases and chronic inflammatory diseases has implicated helminth infections in the prevention of allergy and asthma [see previous reviews (12)(13)(14)]. Helminths produce molecules with powerful immunomodulatory activities such as the anti-inflammatory protein-2 (AIP-2) in hookworms, the transforming growth factor β (TGF-β) mimic (Hp-TGM), the alarmin release inhibitor (Hp-ARI), or the enzyme glutamate dehydrogenase (Hpb-GDH) in the nematode Heligmosomoides polygyrus (15)(16)(17)(18). The anti-inflammatory effects of helminth products observed in experimental models of asthma prompt a better investigation of helminth-(product)-driven regulation of type 2 inflammation and its underlying mechanisms of action in human settings.…”

Immunomodulation and Immune Escape Strategies of Gastrointestinal Helminths and Schistosomes

“…H. bakeri further induces an anti-inflammatory eicosanoid shift in macrophages by secretion of glutamate dehydrogenase (GDH) (24). Macrophages respond to GDH by induced expression of cyclooxygenases and production of prostaglandin E2 (PGE2) which displays some anti-inflammatory functions.…”