IL-33, IL-25 and TSLP contribute to development of fungal-associated protease-induced innate-type airway inflammation

Sci Rep. 2018 Dec 21;8(1):18052. doi: 10.1038/s41598-018-36440-x.


Certain proteases derived from house dust mites and plants are considered to trigger initiation of allergic airway inflammation by disrupting tight junctions between epithelial cells. It is known that inhalation of proteases such as house dust mite-derived Der p1 and/or papaya-derived papain caused airway eosinophilia in naïve mice and even in Rag-deficient mice that lack acquired immune cells such as T, B and NKT cells. In contrast, little is known regarding the possible involvement of proteases derived from Aspergillus species (fungal-associated proteases; FAP), which are ubiquitous saprophytic fungi in the environment, in the development of allergic airway eosinophilia. Here, we found that inhalation of FAP by naïve mice led to airway eosinophilia that was dependent on protease-activated receptor-2 (PAR2), but not TLR2 and TLR4. Those findings suggest that the protease activity of FAP, but not endotoxins in FAP, are important in the setting. In addition, development of that eosinophilia was mediated by innate immune cells (ILCs) such as innate lymphoid cells, but not by acquired immune cells such as T, B and NKT cells. Whereas IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) are involved in induction of FAP-induced ILC-mediated airway eosinophilia, IL-33-rather than IL-25 and/or TSLP-was critical for the eosinophilia in our model. Our findings improve our understanding of the molecular mechanisms involved in induction of airway inflammation by FAP.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allergens / immunology
  • Animals
  • Aspergillus / enzymology
  • Aspergillus / immunology*
  • Aspergillus / metabolism
  • Cytokines / physiology*
  • Immunity, Cellular / physiology
  • Immunity, Innate / physiology*
  • Interleukin-33 / physiology*
  • Interleukins / physiology*
  • Lung Diseases, Fungal / complications
  • Lung Diseases, Fungal / enzymology
  • Lung Diseases, Fungal / genetics
  • Lung Diseases, Fungal / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Peptide Hydrolases / immunology*
  • Peptide Hydrolases / metabolism
  • Pneumonia / genetics
  • Pneumonia / immunology*
  • Pneumonia / metabolism
  • Pulmonary Eosinophilia / genetics
  • Pulmonary Eosinophilia / immunology
  • Thymic Stromal Lymphopoietin


  • Allergens
  • Cytokines
  • Il33 protein, mouse
  • Interleukin-33
  • Interleukins
  • Mydgf protein, mouse
  • Peptide Hydrolases
  • Thymic Stromal Lymphopoietin