title: Integrated innate mechanisms involved in airway allergic inflammation to the serine protease subtilisin.
abstract: 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, protease-activated 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 Ag-promoting 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.
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil; Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and.
authors: Esther
authors: http://orcid.org/0000-0002-5889-7442
authors: E
authors: Florsheim
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and.
authors: Shuang
authors: S
authors: Yu
authors: Department of Biochemistry, Institute of Chemistry, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil.
authors: Ivan
authors: I
authors: Bragatto
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil;
authors: Lucas
authors: L
authors: Faustino
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil;
authors: Eliane
authors: E
authors: Gomes
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil;
authors: Rodrigo N
authors: RN
authors: Ramos
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil;
authors: José Alexandre M
authors: JA
authors: Barbuto
authors: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510; and.
authors: Ruslan
authors: R
authors: Medzhitov
authors: Department of Immunology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, 05508-000 SP Brazil; momrusso@icb.usp.br.
authors: Momtchilo
authors: M
authors: Russo
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology; D000818:Animals; D059366:Asthma, Occupational / Q000276:immunology*; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020860:Subtilisin / Q000276:immunology*; D055815:Young Adult
chemical_list: D000485:Allergens; D020860:Subtilisin