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

• Published in: Nature (London) 2013-11, Vol.503 (7476), p.397-401
• Main Authors: Nakamura, Yuumi, Oscherwitz, Jon, Cease, Kemp B., Chan, Susana M., Muñoz-Planillo, Raul, Hasegawa, Mizuho, Villaruz, Amer E., Cheung, Gordon Y. C., McGavin, Martin J., Travers, Jeffrey B., Otto, Michael, Inohara, Naohiro, Núñez, Gabriel
• Format: Article
• Language: English
• Subjects: 631/250/254; 64; 64/60; 96; Animals; Atopic dermatitis; Bacterial Toxins - metabolism; Bacterial Toxins - pharmacology; Calcium Signaling - drug effects; Cell Degranulation - drug effects; Culture Media, Conditioned - pharmacology; Dermatitis, Atopic - immunology; Dermatitis, Atopic - metabolism; Dermatitis, Atopic - microbiology; Dermatitis, Atopic - pathology; Diagnosis; Female; Genetic aspects; Health aspects; Humanities and Social Sciences; Immunoglobulin E; Immunoglobulin E - biosynthesis; Immunoglobulin E - immunology; Inflammation - immunology; Inflammation - metabolism; Inflammation - microbiology; Inflammation - pathology; Interleukin-4 - immunology; Intracellular Signaling Peptides and Proteins - metabolism; letter; Male; Mast cells; Mast Cells - cytology; Mast Cells - drug effects; Mice; multidisciplinary; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins c-kit - genetics; Proto-Oncogene Proteins c-kit - metabolism; Science; Skin diseases; Staphylococcus; Staphylococcus aureus - metabolism; Staphylococcus aureus - pathogenicity; Syk Kinase
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/nature12655

Staphylococcus aureus δ-toxin is an inducer of mast cell degranulation in mice and is important for promoting inflammatory skin disease. Bacterial link in common 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 countries 1 . 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 2 . Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis 3 . 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 4 . 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 5 . Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis 6 . 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 (Ca 2+ ) 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