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 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 _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. Access through your

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BEING VIEWED BY OTHERS STREPTOCOCCAL PYROGENIC EXOTOXIN B CLEAVES GSDMA AND TRIGGERS PYROPTOSIS Article 02 February 2022 STAPHYLOCOCCAL PHOSPHATIDYLGLYCEROL ANTIGENS ACTIVATE HUMAN T CELLS

VIA CD1A Article 22 December 2022 PHOSPHATIDYLINOSITOL-SPECIFIC PHOSPHOLIPASE C ENHANCES EPIDERMAL PENETRATION BY _STAPHYLOCOCCUS AUREUS_ Article Open access 20 October 2020 REFERENCES *

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microbial ecology of the murine gastrointestinal tract. _Infect. Immun._ 76, 907–915 (2008) Article  CAS  Google Scholar  Download references 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. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * 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 * Department

of Internal Medicine, Division of Hematology/Oncology, University of Michigan Medical School, Ann Arbor, 48109, Michigan, USA Jon Oscherwitz & Kemp B. Cease * VA Ann Arbor Healthcare

System, 2215 Fuller Road, Ann Arbor, 48105, Michigan, USA Jon Oscherwitz & Kemp B. Cease * 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 * Department of Microbiology and Immunology, and Centre

for Human Immunology, Western University, University of Western Ontario, London, Ontario, N6A 5C1, Canada, Martin J. McGavin * Department of Dermatology, Indiana University School of

Medicine, Indianapolis, 46202, Indiana, USA Jeffrey B. Travers Authors * Yuumi Nakamura View author publications You can also search for this author inPubMed Google Scholar * Jon Oscherwitz

View author publications You can also search for this author inPubMed Google Scholar * Kemp B. Cease View author publications You can also search for this author inPubMed Google Scholar *

Susana M. Chan View author publications You can also search for this author inPubMed Google Scholar * Raul Muñoz-Planillo View author publications You can also search for this author

inPubMed Google Scholar * Mizuho Hasegawa View author publications You can also search for this author inPubMed Google Scholar * Amer E. Villaruz View author publications You can also search

for this author inPubMed Google Scholar * Gordon Y. C. Cheung View author publications You can also search for this author inPubMed Google Scholar * Martin J. McGavin View author

publications You can also search for this author inPubMed Google Scholar * Jeffrey B. Travers View author publications You can also search for this author inPubMed Google Scholar * Michael

Otto View author publications You can also search for this author inPubMed Google Scholar * Naohiro Inohara View author publications You can also search for this author inPubMed Google

Scholar * Gabriel Núñez View author publications You can also search for this author inPubMed Google Scholar 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. CORRESPONDING AUTHOR Correspondence to Gabriel Núñez.

ETHICS DECLARATIONS COMPETING INTERESTS The authors declare no competing financial interests. SUPPLEMENTARY INFORMATION SUPPLEMENTARY INFORMATION This file contains Supplementary Table 1 and

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PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE 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 Download citation * Received: 12 November 2012 * Accepted: 12 September 2013 * Published: 30 October

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