Integrated innate mechanisms involved in airway allergic inflammation to the serine protease subtilisin

Esther Florsheim, Shuang Yu, Ivan Bragatto, Lucas Faustino, Eliane Gomes, Rodrigo N. Ramos, José Alexandre M. Barbuto, Ruslan Medzhitov, Momtchilo Russo

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Proteases are recognized environmental allergens, but little is known about the mechanisms responsible for sensing enzyme activity and initiating the development of allergic inflammation. Because usage of the serine protease subtilisin in the detergent industry resulted in an outbreak of occupational asthma in workers, we sought to develop an experimental model of allergic lung inflammation to subtilisin and to determine the immunological mechanisms involved in type 2 responses. By using a mouse model of allergic airway disease, we have defined in this study that s.c. or intranasal sensitization followed by airway challenge to subtilisin induces prototypic allergic lung inflammation, characterized by airway eosinophilia, type 2 cytokine release, mucus production, high levels of serum IgE, and airway reactivity. These allergic responses were dependent on subtilisin protease activity, proteaseactivated receptor-2, IL-33R ST2, and MyD88 signaling. Also, subtilisin stimulated the expression of the proallergic cytokines IL-1α, IL-33, thymic stromal lymphopoietin, and the growth factor amphiregulin in a human bronchial epithelial cell line. Notably, acute administration of subtilisin into the airways increased lung IL-5-producing type 2 innate lymphoid cells, which required protease-activated receptor-2 expression. Finally, subtilisin activity acted as a Th2 adjuvant to an unrelated airborne Agpromoting allergic inflammation to inhaled OVA. Therefore, we established a murine model of occupational asthma to a serine protease and characterized the main molecular pathways involved in allergic sensitization to subtilisin that potentially contribute to initiate allergic airway disease.

Original languageEnglish (US)
Pages (from-to)4621-4630
Number of pages10
JournalJournal of Immunology
Issue number10
StatePublished - May 15 2015
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology


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