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

2013; Nature Portfolio; Volume: 503; Issue: 7476 Linguagem: Inglês

10.1038/nature12655

1476-4687

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

Allergic Rhinitis and Sensitization

Staphylococcus aureus δ-toxin is an inducer of mast cell degranulation in mice and is important for promoting inflammatory skin disease. The pathogenesis of atopic dermatitis, a chronic inflammatory skin disease, is not fully understood. The condition is known to be mediated by an abnormal IgE immune response in the setting of skin barrier dysfunction and mast-cell activation. And intriguingly, in more than 90% of atopic dermatitis patients the skin lesions are colonized by Staphylococcus aureus. This study identifies a probable mechanistic link between S. aureus and allergic skin disease. Gabriel Nüñez and colleagues show that δ-toxin produced by the bacterium induces mast-cell degranulation and inflammatory skin disease in mice, and that both the IgE response and signs of dermatitis were suppressed in mast-cell-deficient mice. 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.