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Staphylococcus δ-toxin induces allergic skin disease by activating mast cells

Nature volume 503, pages 397–401 (2013)Cite this article

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Abstract

Atopic dermatitis is a chronic inflammatory skin disease that affects 15–30% of children and approximately 5% of adults in industrialized countries1. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction2. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis3. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence4. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen5. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis6. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium (Ca2+) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by δ-toxin was abrogated in KitW-sh/W-sh mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.

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Figure 1: S. aureus δ-toxin induces MC degranulation in vitro and in vivo.
Figure 2: MC degranulation induced by δ-toxin depends on Ca2+ influx/phosphoinositide 3-kinase pathway, but is independent of Syk.
Figure 3: Antigen-independent IgE signalling enhances δ-toxin-induced MC activation.
Figure 4: Staphyloccocus δ-toxin promotes IgE production and inflammatory skin disease by mast cells.

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Acknowledgements

We thank S. Koonse for animal husbandry, J. Whitfield for enzyme-linked immunosorbent assays, S. Meshinchi for electron microscopy, V. Basrur for mass spectrometry, K. Kidwell for advice with statistical analysis, M. K. Oyoshi and R. S. Geha for experimental advice, V. Y. Tan for help with constructing the LAC P3-lux strain and A. Burberry for reviewing the manuscript. Y.N. was supported by fellowships from the Chiba University Global COE Program, the Cell Science Research Foundation and the Kanae Foundation for the Promotion of Medical Science. J.O. and K.B.C. were supported by Department of Veterans Affairs Merit Award I01BX000429. A.E.V., G.Y.C.C. and M.O. were supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH). This work supported by NIH grants R01AR059688 to G.N. and R01HL062996 to J.B.T. and funds to the Michigan Comprehensive Cancer Center Immunology Monitoring Core from the University of Michigan’s Cancer Center Support Grant.

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Authors and Affiliations

  1. Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Yuumi Nakamura, Susana M. Chan, Raul Muñoz-Planillo, Mizuho Hasegawa, Naohiro Inohara & Gabriel Núñez

  2. Department of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA

    Jon Oscherwitz & Kemp B. Cease

  3. VA Ann Arbor Healthcare System, 2215 Fuller Road, Ann Arbor, 48105, Michigan, USA

    Jon Oscherwitz & Kemp B. Cease

  4. Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, US National Institutes of Health, Bethesda, 20892, Maryland, USA

    Amer E. Villaruz, Gordon Y. C. Cheung & Michael Otto

  5. Department of Microbiology and Immunology, and Centre for Human Immunology, Western University, University of Western Ontario, London, Ontario, N6A 5C1, Canada,

    Martin J. McGavin

  6. Department of Dermatology, Indiana University School of Medicine, Indianapolis, 46202, Indiana, USA

    Jeffrey B. Travers

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Contributions

Y.N., N.I. and G.N. designed the research. Y.N. conducted the experiments and analysed data with the help of R.M.-P., S.M.C. and M.H. J.O., K.B.C., J.B.T. and M.J.M. generated and provided critical reagents or material. A.E.V, G.Y.C.C. and M.O. engineered bacterial strains. Y.N. and G.N. wrote the manuscript. All authors discussed the results and commented on the manuscript.

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Correspondence to Gabriel Núñez.

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Nakamura, Y., Oscherwitz, J., Cease, K. et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature 503, 397–401 (2013). https://doi.org/10.1038/nature12655

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