Jill Noll1, Elena Helk1, Helena Fehling1, Hannah Bernin1, Claudia Marggraff1, Thomas Jacobs1, Samuel Huber2, Penelope Pelczar2, Thomas Ernst3, Harald Ittrich3, Benjamin Otto4, Hans-Willi Mittrücker5, Christoph Hölscher6, Frank Tacke7, Iris Bruchhaus1, Egbert Tannich1, Hannelore Lotter8. 1. Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. 2. Department of Molecular Immunology and Gastroenterology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 3. Department and Clinic for Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 4. Department of Bioinformatics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 5. Institute of Immunology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 6. Division of Infection Immunology, Research Center Borstel, Borstel, Germany. 7. Department of Medicine III, University Hospital Aachen, Aachen, Germany. 8. Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. Electronic address: lotter@bnitm.de.
Abstract
BACKGROUND & AIMS: The IL-23/IL-17 axis plays an important role in the pathogenesis of autoimmune diseases and the pathological consequences of infection. We previously showed that immunopathologic mechanisms mediated by inflammatory monocytes underlie the severe focal liver damage induced by the protozoan parasite, Entamoeba histolytica. Here, we analyze the contribution of the IL-23/IL-17 axis to the induction and subsequent recovery from parasite-induced liver damage. METHODS: IL-23p19(-/-), IL-17A/F(-/-), CCR2(-/-), and wild-type (WT) mice were intra-hepatically infected with E. histolytica trophozoites and disease onset and recovery were analyzed by magnetic resonance imaging. Liver-specific gene and protein expression during infection was examined by qPCR, microarray, FACS analysis and immunohistochemistry. Immuno-depletion and substitution experiments were performed in IL-23p19(-/-) and WT mice to investigate the role of IL-13 in disease outcome. RESULTS: Liver damage in infected IL-23p19(-/-), IL-17A/F(-/-), and CCR2(-/-) mice was strongly attenuated compared with that in WT mice. IL-23p19(-/-) mice showed reduced accumulation of IL-17 and CCL2 mRNA and proteins. Increased numbers of IL-13-producing CD11b(+)Ly6C(lo) monocytes were associated with disease attenuation in IL-23p19(-/-) mice. Immuno-depletion of IL-13 in IL-23p19(-/-) mice reversed this attenuation and treatment of infected WT mice with an IL-13/anti-IL-13-mAb complex supported liver recovery. CONCLUSIONS: The IL-23/IL-17 axis plays a critical role in the immunopathology of hepatic amebiasis. IL-13 secreted by CD11b(+)Ly6C(lo) monocytes may be associated with recovery from liver damage. An IL-13/anti-IL13-mAb complex mimics this function, suggesting a novel therapeutic option to support tissue healing after liver damage.
BACKGROUND & AIMS: The IL-23/IL-17 axis plays an important role in the pathogenesis of autoimmune diseases and the pathological consequences of infection. We previously showed that immunopathologic mechanisms mediated by inflammatory monocytes underlie the severe focal liver damage induced by the protozoan parasite, Entamoeba histolytica. Here, we analyze the contribution of the IL-23/IL-17 axis to the induction and subsequent recovery from parasite-induced liver damage. METHODS:IL-23p19(-/-), IL-17A/F(-/-), CCR2(-/-), and wild-type (WT) mice were intra-hepatically infected with E. histolyticatrophozoites and disease onset and recovery were analyzed by magnetic resonance imaging. Liver-specific gene and protein expression during infection was examined by qPCR, microarray, FACS analysis and immunohistochemistry. Immuno-depletion and substitution experiments were performed in IL-23p19(-/-) and WT mice to investigate the role of IL-13 in disease outcome. RESULTS:Liver damage in infected IL-23p19(-/-), IL-17A/F(-/-), and CCR2(-/-) mice was strongly attenuated compared with that in WT mice. IL-23p19(-/-) mice showed reduced accumulation of IL-17 and CCL2 mRNA and proteins. Increased numbers of IL-13-producing CD11b(+)Ly6C(lo) monocytes were associated with disease attenuation in IL-23p19(-/-) mice. Immuno-depletion of IL-13 in IL-23p19(-/-) mice reversed this attenuation and treatment of infected WTmice with an IL-13/anti-IL-13-mAb complex supported liver recovery. CONCLUSIONS: The IL-23/IL-17 axis plays a critical role in the immunopathology of hepatic amebiasis. IL-13 secreted by CD11b(+)Ly6C(lo) monocytes may be associated with recovery from liver damage. An IL-13/anti-IL13-mAb complex mimics this function, suggesting a novel therapeutic option to support tissue healing after liver damage.
Authors: Julie Sellau; Marie Groneberg; Helena Fehling; Thorsten Thye; Stefan Hoenow; Claudia Marggraff; Marie Weskamm; Charlotte Hansen; Stephanie Stanelle-Bertram; Svenja Kuehl; Jill Noll; Vincent Wolf; Nahla Galal Metwally; Sven Hendrik Hagen; Christoph Dorn; Julia Wernecke; Harald Ittrich; Egbert Tannich; Thomas Jacobs; Iris Bruchhaus; Marcus Altfeld; Hannelore Lotter Journal: Nat Commun Date: 2020-07-10 Impact factor: 14.919
Authors: Csenge Pajtók; Apor Veres-Székely; Róbert Agócs; Beáta Szebeni; Péter Dobosy; István Németh; Zoltán Veréb; Lajos Kemény; Attila J Szabó; Ádám Vannay; Tivadar Tulassay; Domonkos Pap Journal: PLoS One Date: 2021-11-01 Impact factor: 3.240