title: Staphylococcus δ-toxin induces allergic skin disease by activating mast cells.
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 (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 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.
authors.affiliation: Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.
authors.forename: Yuumi
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Jon
authors.initials: J
authors.lastname: Oscherwitz
authors.forename: Kemp B
authors.initials: KB
authors.lastname: Cease
authors.forename: Susana M
authors.initials: SM
authors.lastname: Chan
authors.forename: Raul
authors.initials: R
authors.lastname: Muñoz-Planillo
authors.forename: Mizuho
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Amer E
authors.initials: AE
authors.lastname: Villaruz
authors.forename: Gordon Y C
authors.initials: GY
authors.lastname: Cheung
authors.forename: Martin J
authors.initials: MJ
authors.lastname: McGavin
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Travers
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.forename: Naohiro
authors.initials: N
authors.lastname: Inohara
authors.forename: Gabriel
authors.initials: G
authors.lastname: Núñez
mesh_terms: D000818:Animals; D001427:Bacterial Toxins / Q000378:metabolism* / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D015550:Cell Degranulation / Q000187:drug effects; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003876:Dermatitis, Atopic / Q000276:immunology / Q000378:metabolism / Q000382:microbiology* / Q000473:pathology; D005260:Female; D007073:Immunoglobulin E / Q000096:biosynthesis / Q000276:immunology; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000473:pathology; D015847:Interleukin-4 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008407:Mast Cells / Q000166:cytology* / Q000187:drug effects; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics / Q000378:metabolism; D013211:Staphylococcus aureus / Q000378:metabolism / Q000472:pathogenicity*; D000072377:Syk Kinase
chemical_list: D001427:Bacterial Toxins; D017077:Culture Media, Conditioned; D047908:Intracellular Signaling Peptides and Proteins; C025971:staphylococcal delta toxin; D015847:Interleukin-4; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D019009:Proto-Oncogene Proteins c-kit; D000072377:Syk Kinase; C000606897:Syk protein, mouse