A helminth glutamate dehydrogenase targets eicosanoid pathways to modulate type-2 immunity

Bioactive metabolites of arachidonic acid control chronic inflammation, particularly in therapy-resistant airway diseases. Helminth products have been suggested as natural immunoregulators for treating inflammatory diseases. Here, we identified an anti-inflammatory glutamate dehydrogenase (GDH) in the larval extract of the helminth Heligmosomoides polygyrus bakeri (Hpb). We particularly assessed whether Hpb GDH regulates type 2 immune responses by modulating immune cell metabolism. Effects of Hpb GDH on the metabolism of monocyte derived macrophages (MDM), were quantified by mediator profiling by LC-MS/MS (eicosanoids, TCA metabolites) and seahorse analysis. Moreover, Hpb GDH treated MDM were subjected to RNA sequencing to assess effects on gene expression profile. For characterization of immune regulatory effects in vivo, mice were treated with Hpb GDH during house dust mite (HDM)-induced allergic airway inflammation or during infection with Hpb. In macrophages, Hpb GDH induced the production of prostanoids and 2-hydroxyglutarate, which contributed to the suppression of cysteinyl leukotrienes. Moreover, Hpb GDH treated MDM showed an induction of regulatory and type 2 suppressive genes, which partially depended on histone acetylation via p300 HAT. Treatment of mice with Hpb GDH attenuated allergic airway inflammation in mice, while treatment during Hpb infection results in a significant increase in worm burden, suggesting that Hpb GDH regulates type 2 immune responses by modulating the metabolism as well as gene expression in macrophages. Thus, anti-inflammatory modulation of macrophages by Hpb GDH may be translated into new immunomodulatory strategies for the treatment of airway diseases.