Role of Allergen Source-Derived Proteases in Sensitization via Airway Epithelial Cells

Abstract

Protease activity is a characteristic common to many allergens. Allergen source-derived proteases interact with lung epithelial cells, which are now thought to play vital roles in both innate and adaptive immune responses. Allergen source-derived proteases act on airway epithelial cells to induce disruption of the tight junctions between epithelial cells, activation of protease-activated receptor-2, and the production of thymic stromal lymphopoietin. These facilitate allergen delivery across epithelial layers and enhance allergenicity or directly activate the immune system through a nonallergic mechanism. Furthermore, they cleave regulatory cell surface molecules involved in allergic reactions. Thus, allergen source-derived proteases are a potentially critical factor in the development of allergic sensitization and appear to be strongly associated with heightened allergenicity.

Figure 1

Allergen source-derived proteases compromise epithelial barrier function by degrading TJ proteins, facilitating allergen accessibility to DCs. Enzymatically active allergens can activate PAR to induce TSLP. TSLP induces immediate innate immune functions in DCs, leading to recruitment of inflammatory cells. TSLP triggers the maturation of DCs, so they migrate to mediastinal lymph nodes. Induction of DCs to upregulate OX40L by TSLP promotes Th2 responses. PAR also upregulates production of MMP-9, which degrades tight junction proteins. Thus, impairment of airway epithelial barrier function and activation of epithelial cells are involved in the pathogenesis of inflammation mediated by allergen source-derived proteases.