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 here that subcutaneous or intranasal sensitization followed by airway challenge to subtilisin induces prototypic allergic lung inflammation, characterized by airway eosinophilia, type 2 cytokines release, mucus production, high levels of serum IgE, and airway reactivity. These allergic responses were dependent on subtilisin protease activity, protease-activated receptor (PAR)-2, IL-33 receptor ST2, and MyD88 signaling. Also, subtilisin stimulated the expression of the pro-allergic cytokines IL-1α, IL-33, TSLP, 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 PAR-2 expression. Finally, subtilisin activity acted as a Th2 adjuvant to an unrelated airborne antigen 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.

Occupational Exposure to Bioaerosols in Norwegian Crab Processing Plants

“…A previous study found that there is trypsin and trypsin-like enzyme activity in extracted tissue samples from crustaceans (Sun and Lopata 2010), but there are no previous publications that have quantified the level of airborne trypsin activity during seafood processing. Trypsin is a common serine protease enzyme and inhaled by workers may have an immunological or non-immunological effect on the lungs (Sun and Lopata 2010;Baur 2005;Florsheim et al 2015;Madsen et al 2015). Optimal conditions for several crustacean trypsins are around 40˚C and pH6, which is close to the physiological conditions found in human lungs (Sun and Lopata 2010).…”

Allergen-encoded signals that control allergic responses

“…1). Florsheim et al [18 ▪▪ ] recently showed that subtilisin, a bacterial-derived proteinase that is widely used in laundry detergents and has long been linked to human allergic disease, induces airway epithelial TSLP and IL-33 in mice.…”

Biological and chemical hazards in water-mix metalworking fluids and mists

“…Despite the longstanding association between proteases and respiratory disease, the mechanisms responsible for initiating allergic inflammation is still at an early stage of investigation (Florsheim et al, 2015). Since microbial contaminants are common in MWF, it is possible that bacterial proteases will also be present, but there is no 58 published evidence to support this hypothesis.…”

“…They were associated with OA in various occupations such as flour bakeries, food processing (Stobnicka and Gorny, 2015), industrial enzyme manufacture and the cleaning industry (Adisesh et al, 2011). Most notably in the cleaning industry when the heat stable alkaline protease Carlsberg subtilisin was added to detergents to aid nonchemical cleaning actions (Florsheim et al, 2015). Subsequently up to 50% of the employees developed allergic asthma (Florsheim et al, 2015).…”

“…Most notably in the cleaning industry when the heat stable alkaline protease Carlsberg subtilisin was added to detergents to aid nonchemical cleaning actions (Florsheim et al, 2015). Subsequently up to 50% of the employees developed allergic asthma (Florsheim et al, 2015).…”