Antigen Protease Activity on Intact or Tape-Stripped Skin Induces Acute Itch and T Helper Sensitization Leading to Airway Eosinophilia in Mice

Toru Kimitsu; Seiji Kamijo; Tomoko Yoshimura; Yurie Masutani; Saya Shimizu; Keiko Takada; Punyada Suchiva; Hideoki Ogawa; Ko Okumura; Shigaku Ikeda; Toshiro Takai

doi:10.1016/j.xjidi.2023.100239

Antigen Protease Activity on Intact or Tape-Stripped Skin Induces Acute Itch and T Helper Sensitization Leading to Airway Eosinophilia in Mice

JID Innov. 2023 Oct 5;4(1):100239. doi: 10.1016/j.xjidi.2023.100239. eCollection 2024 Jan.

Authors

Toru Kimitsu^{1

2}, Seiji Kamijo¹, Tomoko Yoshimura^{1

2}, Yurie Masutani^{1

2}, Saya Shimizu¹, Keiko Takada^{1

2}, Punyada Suchiva^{1

2}, Hideoki Ogawa², Ko Okumura¹, Shigaku Ikeda^{1

2}, Toshiro Takai¹

Affiliations

¹ Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
² Department of Dermatology and Allergology, Juntendo University Graduate School of Medicine, Tokyo, Japan.

Abstract

Respiratory allergen sources such as house dust mites frequently contain proteases. In this study, we demonstrated that the epicutaneous application of a model protease antigen, papain, onto intact or tape-stripped ear skin of mice induced acute scratching behaviors and T helper (Th)2, Th9, Th17/Th22, and/or Th1 sensitization in a protease activity-dependent manner. The protease activity of papain applied onto the skin was also essential for subsequent airway eosinophilia induced by an intranasal challenge with low-dose papain. With tape stripping, papain-treated mice showed barrier dysfunction, the accelerated onset of acute scratching behaviors, and attenuated Th17/Th22 sensitization. In contrast, the protease activity of inhaled papain partially or critically contributed to airway atopic march responses in mice sensitized through intact or tape-stripped skin, respectively. These results indicated that papain protease activity on epicutaneous application through intact skin or skin with mechanical barrier damage is critical to the sensitization phase responses, including acute itch and Th sensitization and progression to the airway atopic march, whereas dependency on the protease activity of inhaled papain in the atopic march differs by the condition of the sensitized skin area. This study suggests that exogenous protease-dependent epicutaneous mechanisms are a target for controlling allergic sensitization and progression to the atopic march.

Keywords: Acute itch; Atopic march; Murine model; Protease antigen; Th sensitization.