Repeated sensitization of mice with microfilariae of Litomosoides sigmodontis induces pulmonary eosinophilia in an IL-33-dependent manner

Benjamin Lenz, Alexandra Ehrens, Jesuthas Ajendra, Frederic Risch, Joséphine Gal, Anna-Lena Neumann, Julia J. Reichwald, Wiebke Strutz, Henry J. McSorley, Coralie Martin, Achim Hoerauf, Marc P. Hübner (Lead / Corresponding author)

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Abstract

Background Eosinophilia is a hallmark of helminth infections and eosinophils are essential in the protective immune responses against helminths. Nevertheless, the distinct role of eosinophils during parasitic filarial infection, allergy and autoimmune disease-driven pathology is still not sufficiently understood. In this study, we established a mouse model for microfilariae-induced eosinophilic lung disease (ELD), a manifestation caused by eosinophil hyper-responsiveness within the lung. Methods Wild-type (WT) BALB/c mice were sensitized with dead microfilariae (MF) of the rodent filarial nematode Litomosoides sigmodontis three times at weekly intervals and subsequently challenged with viable MF to induce ELD. The resulting immune response was compared to non-sensitized WT mice as well as sensitized eosinophil-deficient dblGATA mice using flow cytometry, lung histology and ELISA. Additionally, the impact of IL-33 signaling on ELD development was investigated using the IL-33 antagonist HpARI2. Results ELD-induced WT mice displayed an increased type 2 immune response in the lung with increased frequencies of eosinophils, alternatively activated macrophages and group 2 innate lymphoid cells, as well as higher peripheral blood IgE, IL-5 and IL-33 levels in comparison to mice challenged only with viable MF or PBS. ELD mice had an increased MF retention in lung tissue, which was in line with an enhanced MF clearance from peripheral blood. Using eosinophil-deficient dblGATA mice, we demonstrate that eosinophils are essentially involved in driving the type 2 immune response and retention of MF in the lung of ELD mice. Furthermore, we demonstrate that IL-33 drives eosinophil activation in vitro and inhibition of IL-33 signaling during ELD induction reduces pulmonary type 2 immune responses, eosinophil activation and alleviates lung lacunarity. In conclusion, we demonstrate that IL-33 signaling is essentially involved in MF-induced ELD development.

Original languageEnglish
Article numbere1012071
Number of pages26
JournalPLoS Pathogens
Volume20
Issue number3
DOIs
Publication statusPublished - 8 Mar 2024

Keywords

  • Humans
  • Animals
  • Mice
  • Microfilariae
  • Pulmonary Eosinophilia
  • Immunity, Innate
  • Filariasis/parasitology
  • Interleukin-33
  • Lymphocytes/pathology
  • Filarioidea/physiology
  • Asthma
  • Eosinophils
  • Mice, Inbred BALB C

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Virology
  • Parasitology
  • Microbiology
  • Immunology

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