Epicutaneous Allergic Sensitization by Cooperation between Allergen Protease Activity and Mechanical Skin Barrier Damage in Mice

Abstract

Allergen sources such as mites, insects, fungi, and pollen contain proteases. Airway exposure to proteases induces allergic airway inflammation and IgE/IgG1 responses via IL-33-dependent mechanisms in mice. We examined the epicutaneous sensitization of mice to a model protease allergen, papain; the effects of tape stripping, which induces epidermal barrier dysfunction; and the atopic march upon a subsequent airway challenge. Papain painting on ear skin and tape stripping cooperatively promoted dermatitis, the skin gene expression of proinflammatory cytokines and growth factors, up-regulation of serum total IgE, and papain-specific IgE/IgG1 induction. Epicutaneous sensitization induced T helper (Th) 2 cells and Th17 differentiation in draining lymph nodes. Ovalbumin and protease inhibitor-treated papain induced no or weak responses, whereas the co-administration of ovalbumin and papain promoted ovalbumin-specific IgE/IgG1 induction. Wild-type and IL-33-deficient mice showed similar responses in the epicutaneous sensitization phase. The subsequent airway papain challenge induced airway eosinophilia and maintained high papain-specific IgE levels in an IL-33-dependent manner. These results suggest that allergen source-derived protease activity and mechanical barrier damage such as that caused by scratching cooperatively promote epicutaneous sensitization and skin inflammation and that IL-33 is dispensable for epicutaneous sensitization but is crucial in the atopic march upon a subsequent airway low-dose encounter with protease allergens.

Epithelial barrier dysfunctions in atopic dermatitis: a skin-gut-lung model linking microbiome alteration and immune dysregulation

“…Various environmental allergens, such as house dust mite, cockroach, fungi and pollen, contain cysteine and serine proteases . The proteolytic allergens can bind protease‐activated receptor on keratinocytes, triggering epidermal degradation and Th2‐mediated inflammation .…”

“…In AD mouse models, epicutaneous sensitization with allergen promotes a local and systemic Th2‐predominant response, characterized by increased IL‐4, IL‐5, IL‐13 and IgE . The combination of papain (a proteolytic antigen) and mechanical barrier damage caused by tape stripping synergistically promote dermatitis and antigen‐specific IgE response . Following epicutaneous sensitization, airway challenge then leads to systemic inflammation characterized by IL‐33‐mediated activation of ILC2, robust eosinophilia and IgE/IgG1 production .…”

“…Various environmental allergens, such as house dust mite, cockroach, fungi and pollen, contain cysteine and serine proteases. 2,32 The proteolytic allergens can bind protease-activated receptor on keratinocytes, triggering epidermal degradation and Th2-mediated inflammation. 2,23 Reduction in serine protease inhibitors, such as serine protease inhibitor Kazal type-5, further enhances protease-activated pathways and contributes to disease aggravation.…”

The Skin as a Route of Allergen Exposure: Part II. Allergens and Role of the Microbiome and Environmental Exposures

“…Similar to the detrimental effects of dysregulated endogenous protease activity discussed previously in part I of this article, exogenous protease activity of house dust mite, insects, fungi, and pollen disrupts intercorneocyte connections, enhancing their behavior as skin allergens [1, 2]. Der f 1 (dust mite allergen), for example, disrupts epidermal tight junctions and induces inflammatory mediator release (IL-6, IL-8, GM-CSF) by keratinocytes [3].…”

Outstanding animal studies in allergy II. From atopic barrier and microbiome to allergen-specific immunotherapy

“…Enzymatically active papain induced immediate inflammation via intact skin in vivo , and it retained the sensitization potential when its enzymatic activity was inhibited [15]. On tape stripped skin, papain acted as adjuvant for another model allergen, ovalbumin [16], and primed specific respiratory hypersensitivity, mirroring the atopic march.…”