Staphylococcus aureus δ-toxin present on skin promotes the development of food allergy in a murine model

Hiromichi Yamada; Ayako Kaitani; Kumi Izawa; Tomoaki Ando; Anna Kamei; Shino Uchida; Akie Maehara; Mayuki Kojima; Risa Yamamoto; Hexing Wang; Masakazu Nagamine; Keiko Maeda; Koichiro Uchida; Nobuhiro Nakano; Yoshikazu Ohtsuka; Hideoki Ogawa; Ko Okumura; Toshiaki Shimizu; Jiro Kitaura

doi:10.3389/fimmu.2023.1173069

Staphylococcus aureus δ-toxin present on skin promotes the development of food allergy in a murine model

Front Immunol. 2023 May 19:14:1173069. doi: 10.3389/fimmu.2023.1173069. eCollection 2023.

Authors

Hiromichi Yamada^{1

2}, Ayako Kaitani¹, Kumi Izawa¹, Tomoaki Ando¹, Anna Kamei^{1

3}, Shino Uchida^{1

4}, Akie Maehara¹, Mayuki Kojima^{1

2}, Risa Yamamoto¹, Hexing Wang^{1

3}, Masakazu Nagamine¹, Keiko Maeda^{1

5}, Koichiro Uchida^{1

6}, Nobuhiro Nakano¹, Yoshikazu Ohtsuka², Hideoki Ogawa¹, Ko Okumura¹, Toshiaki Shimizu^{1

2}, Jiro Kitaura^{1

3}

Affiliations

¹ Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan.
² Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
³ Department of Science of Allergy and Inflammation, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁴ Department of Gastroenterology, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁵ Department of Immunological Diagnosis, Juntendo University Graduate School of Medicine, Tokyo, Japan.
⁶ Juntendo Advanced Research Institute for Health Science, Juntendo University School of Medicine, Tokyo, Japan.

Abstract

Background: Patients with food allergy often suffer from atopic dermatitis, in which Staphylococcus aureus colonization is frequently observed. Staphylococcus aureus δ-toxin activates mast cells and promotes T helper 2 type skin inflammation in the tape-stripped murine skin. However, the physiological effects of δ-toxin present on the steady-state skin remain unknown. We aimed to investigate whether δ-toxin present on the steady-state skin impacts the development of food allergy.

Material and methods: The non-tape-stripped skins of wild-type, Kit^W-sh/W-sh, or ST2-deficient mice were treated with ovalbumin (OVA) with or without δ-toxin before intragastric administration of OVA. The frequency of diarrhea, numbers of jejunum or skin mast cells, and serum levels of OVA-specific IgE were measured. Conventional dendritic cell 2 (cDC2) in skin and lymph nodes (LN) were analyzed. The cytokine levels in the skin tissues or culture supernatants of δ-toxin-stimulated murine keratinocytes were measured. Anti-IL-1α antibody-pretreated mice were analyzed.

Results: Stimulation with δ-toxin induced the release of IL-1α, but not IL-33, in murine keratinocytes. Epicutaneous treatment with OVA and δ-toxin induced the local production of IL-1α. This treatment induced the translocation of OVA-loaded cDC2 from skin to draining LN and OVA-specific IgE production, independently of mast cells and ST2. This resulted in OVA-administered food allergic responses. In these models, pretreatment with anti-IL-1α antibody inhibited the cDC2 activation and OVA-specific IgE production, thereby dampening food allergic responses.

Conclusion: Even without tape stripping, δ-toxin present on skin enhances epicutaneous sensitization to food allergen in an IL-1α-dependent manner, thereby promoting the development of food allergy.

Keywords: IL-1α; IgE; Staphylococcus aureus δ-toxin; epicutaneous sensitization; food allergy; murine model.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Dermatitis, Atopic*
Disease Models, Animal
Exotoxins
Food Hypersensitivity*
Immunoglobulin E
Interleukin-1 Receptor-Like 1 Protein
Mice
Ovalbumin
Staphylococcus aureus

Substances

Interleukin-1 Receptor-Like 1 Protein
Immunoglobulin E
Ovalbumin
Exotoxins

Grants and funding

This study was supported by JSPS KAKENHI Grant (Numbers 17H04217, 20H03721, 19K17895, and 22K15978), a grant from Nakatomi Foundation, and a grant from Nipponham Foundation for the Future of Food, and a Grant-in-Aid for Special Research in Subsidies for ordinary expenses of private schools from The Promotion and Mutual Aid Corporation for Private Schools of Japan.