Rolle und Wirkmechanismus der Glutamatdehydrogenase in der Helminthen-getriebenen Regulation von Eikosanoiden und Typ 2 Immunantworten
Zusammenfassung der Projektergebnisse
Bioactive metabolites of arachidonic acid control chronic inflammation, particularly in therapyresistant airway diseases. Helminth products have been suggested as natural immune regulators for treating inflammatory diseases. In this project, we have 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 profiles of human macrophages. 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 pro-inflammatory cysteinyl leukotrienes, which are key mediators of asthma. Moreover, Hpb GDH treated MDM showed an induction of regulatory and type 2 suppressive genes, which depended on histone acetylation via the p300 histone acetyl transferase. Treatment of mice with Hpb GDH attenuated allergic airway inflammation in mice, while treatment during Hpb infection resulted in a significant increase in worm burdens, suggesting that Hpb GDH regulates type 2 immune responses by modulating the metabolism as well as epigenetic profiles of macrophages. In addition, myeloid cells treated with GDHs from different helminth parasites induced regulatory T-cells in a prostaglandin E2 dependent manner. Finally, neutralization of Hpb GDH with a specific monoclonal antibody resulted in a reduction in worm numbers in the small intestine of helminth infected mice, suggesting that helminth GDH is required for establishing chronic infection. Thus, the suppression of anti-helminth immunity by helminthic glutamate dehydrogenases represents a newly identified mechanism of immune evasion. The anti-inflammatory modulation of macrophages by Hpb GDH may be translated into new immunomodulatory strategies for the treatment of inflammatory diseases such as allergy or asthma.
Projektbezogene Publikationen (Auswahl)
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(2020), An anti-inflammatory eicosanoid switch mediates the suppression of type-2 inflammation by helminth larval products, Science Translational Medicine, 12(540)
de Los Reyes Jiménez M, Lechner A, Alessandrini F, Schindela S, Trompette A, Haimerl P, Thomas D, Haslbeck M, Henkel FDR, Prazeres da Costa C, Feige MJ, Chaker AM, Dehne N, Brüne B, Nüsing R, Nockher WA, Ohnmacht C, Marsland BJ, Harris NL, Schmidt-Weber CB, Esser-von Bieren J
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(2020), What Can Parasites Tell Us About the Pathogenesis and Treatment of Asthma and Allergic Diseases, Front Immunol. Sep 11;11:2106
Bohnacker S, Troisi F, de Los Reyes Jiménez M, Esser-von Bieren J
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(2021), Macrophage regulation & function in helminth infection, Sem Immunol., 7(67); 53:101526
Lechner A, Bohnacker S, Esser-von Bieren J
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(2022). Helminthic dehydrogenase drive PGE2 and IL-10 production in monocytes to potentiate Treg induction. EMBO Rep., 23(5):e54096
Prodjinotho UF, Gres V, Henkel FDR, Lacorcia M, Dandl R, Haslbeck M, Schmidt V, Winkler AS, Sikasunge C, Jakobsson PJ, Henneke P, Esser-von Bieren J, Prazeres da Costa C
