Nematode ascarosides attenuate mammalian type 2 inflammatory responses

Area of Science:

• Immunology
• Parasitology
• Allergy Research

Background:

• Nematode infections show protective effects against immune dysregulation disorders like asthma.
• Excretory/secretory (ES) products from nematodes have demonstrated therapeutic potential in animal models, but active small molecules remain unidentified.
• Concerns exist regarding live parasite ingestion and protein immunogenicity in human trials.

Purpose of the Study:

• To identify small molecules from nematodes with immune regulatory activity.
• To investigate the therapeutic potential of nematode-derived small molecules in asthma models.
• To elucidate the mechanism by which these molecules modulate the pulmonary immune response.

Main Methods:

• Screening of ascarosides, a family of nematode pheromones, for inhibitory effects on asthma development in an ovalbumin (OVA) murine model.
• Administration of ascr#7 to mice to assess its impact on lung inflammation and airway hyperreactivity.
• Analysis of cytokine production (e.g., IL-33) and immune cell populations (Th2 cells, ILC2s) in the lungs.

Main Results:

• Nanogram quantities of ascr#7 significantly prevented lung eosinophilia, goblet cell metaplasia, and airway hyperreactivity in a murine asthma model.
• Ascr#7 suppressed interleukin-33 (IL-33) production from lung epithelial cells.
• Ascr#7 reduced the number of pathogenic Th2 cells and innate lymphoid cells type 2 (ILC2s) in the lungs.

Conclusions:

• Ascarosides, specifically ascr#7, are evolutionarily conserved molecules recognized by the mammalian immune system as a signature of parasitic nematodes.
• The identification of ascr#7 provides a novel, small-molecule therapeutic candidate for allergic diseases.
• This finding opens avenues for developing new treatments for asthma and other immune dysregulation disorders based on nematode-derived compounds.