Staphylococcus aureus second immunoglobulin-binding protein drives atopic dermatitis via IL-33

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:147

Article

Al Kindi, Arwa¹  Williams, Helen¹  Matsuda, Kenshiro²  Alkahtani, Abdullah M.³  Saville, Charis¹  Bennett, Hayley⁴  Alshammari, Yasmine¹  Tan, Soo Y.⁵  O'Neill, Catherine⁶  Tanaka, Akane⁷  Matsuda, Hiroshi⁸  Arkwright, Peter D.¹  Pennock, Joanne L.¹ 

[1] Univ Manchester, Lydia Becker Inst Immunol & Inflammat, Manchester, Lancs, England

[2] Univ Tsukuba, Ctr Innovat Drug Discovery, Tsukuba, Ibaraki, Japan

[3] King Khalid Univ, Dept Med Microbiol & Parasitol, Abha, Saudi Arabia

[4] Univ Manchester, Genome Editing Unit, Manchester, Lancs, England

[5] Natl Univ Hlth Syst, Singapore, Singapore

[6] Univ Manchester, Div Dermatol & Musculoskeletal Sci, Manchester, Lancs, England

[7] Tokyo Univ Agr & Technol, Lab Comparat Anim Med, Tokyo, Japan

[8] Tokyo Univ Agr & Technol, Lab Vet Mol Pathol & Therapeut, Tokyo, Japan

关键词: Staphylococcus aureus;    atopic dermatitis;    second immunoglobulin-binding protein;    Sbi;    virulence factor;    skin;    kerati-nocytes;    IL-33;    TSLP;    type 2 immune response;   

DOI  :  10.1016/j.jaci.2020.09.023

来源: Elsevier

【 摘 要 】

Background: Staphylococcus aureus is the dominant infective trigger of atopic dermatitis (AD). How this bacterium drives type 2 allergic pathology in the absence of infection in patients with AD is unclear. Objective: We sought to identify the S aureus?derived virulence factor(s) that initiates the cutaneous type 2-promoting immune response responsible for AD. Methods: In vitro human keratinocyte cell culture, ex vivo human skin organ explants, and the eczema-prone Nishikinezumi Cinnamon/Tokyo University of Agriculture and Technology strain mouse were used as model systems to assess type 2-promoting immune responses to S aureus. Identification of the bioactive factor was accomplished using fast protein liquid chromatography and mass spectrometry. Bioactivity was confirmed by cloning and expression in an Escherichia coli vector system, and S aureus second immunoglobulin-binding protein (Sbi) mutant strains confirming loss of activity. Results: S aureus was unique among staphylococcal species in its ability to induce the rapid release of constitutive IL-33 from human keratinocytes independent of the Toll-like receptor pathway. Using the eczema-prone Nishiki-nezumi Cinnamon/ Tokyo University of Agriculture and Technology strain mouse model, we showed that IL-33 was essential for inducing the immune response to S aureus in vivo. By fractionation and candidate testing, we identified Sbi as the predominant staphylococcus-derived virulence factor that directly drives IL-33 release from human keratinocytes. Immunohistology of skin demonstrated that corneodesmosin, a component of corneodesmosomes that form key intercellular adhesive structures in the stratum corneum, was disrupted, resulting in reduction of skin barrier function. Conclusions: S aureus-derived Sbi is a unique type 2-promoting virulence factor capable of initiating the type 2-promoting cytokine activity underlying AD. (J Allergy Clin Immunol 2021;147:1354-68.)

【 授权许可】

Free