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

Yuumi Nakamura, Jon Oscherwitz, Kemp B. Cease, Susana M. Chan, Raul Muñoz-Planillo, Mizuho Hasegawa, Amer E. Villaruz, Gordon Y.C. Cheung, Martin J. McGavin, Jeffrey B. Travers, Michael Otto, Naohiro Inohara, Gabriel Núñez

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204 Scopus citations

Abstract

Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. 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 dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. 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 defence. 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 pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. 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 Kit W-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.

Original languageEnglish (US)
Pages (from-to)397-401
Number of pages5
JournalNature
Volume503
Issue number7476
DOIs
StatePublished - Nov 6 2013

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Nakamura, Y., Oscherwitz, J., Cease, K. B., Chan, S. M., Muñoz-Planillo, R., Hasegawa, M., Villaruz, A. E., Cheung, G. Y. C., McGavin, M. J., Travers, J. B., Otto, M., Inohara, N., & Núñez, G. (2013). Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature, 503(7476), 397-401. https://doi.org/10.1038/nature12655