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 Travers, Michael Otto, Naohiro Inohara, Gabriel Núñez

Research output: Contribution to journalArticle

173 Citations (Scopus)

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
Pages (from-to)397-401
Number of pages5
JournalNature
Volume503
Issue number7476
DOIs
StatePublished - 2013

Fingerprint

Staphylococcus
Skin Diseases
Mast Cells
Atopic Dermatitis
Cell Degranulation
Immunoglobulin E
Staphylococcus aureus
Exotoxins
Skin
Antigens
Superantigens
1-Phosphatidylinositol 4-Kinase
Dermatitis
Helper-Inducer T-Lymphocytes
Developed Countries
Interleukin-4
Calcium
Membranes

ASJC Scopus subject areas

  • General

Cite this

Nakamura, Y., Oscherwitz, J., Cease, K. B., Chan, S. M., Muñoz-Planillo, R., Hasegawa, M., ... 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

Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. / 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; Otto, Michael; Inohara, Naohiro; Núñez, Gabriel.

In: Nature, Vol. 503, No. 7476, 2013, p. 397-401.

Research output: Contribution to journalArticle

Nakamura, Y, Oscherwitz, J, Cease, KB, Chan, SM, Muñoz-Planillo, R, Hasegawa, M, Villaruz, AE, Cheung, GYC, McGavin, MJ, Travers, J, Otto, M, Inohara, N & Núñez, G 2013, 'Staphylococcus δ-toxin induces allergic skin disease by activating mast cells', Nature, vol. 503, no. 7476, pp. 397-401. https://doi.org/10.1038/nature12655
Nakamura Y, Oscherwitz J, Cease KB, Chan SM, Muñoz-Planillo R, Hasegawa M et al. Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. Nature. 2013;503(7476):397-401. https://doi.org/10.1038/nature12655
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 ; Otto, Michael ; Inohara, Naohiro ; Núñez, Gabriel. / Staphylococcus δ-toxin induces allergic skin disease by activating mast cells. In: Nature. 2013 ; Vol. 503, No. 7476. pp. 397-401.
@article{4262ec85b56340cfbe14c3a1b700ddcd,
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 (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.",
author = "Yuumi Nakamura and Jon Oscherwitz and Cease, {Kemp B.} and Chan, {Susana M.} and Raul Mu{\~n}oz-Planillo and Mizuho Hasegawa and Villaruz, {Amer E.} and Cheung, {Gordon Y C} and McGavin, {Martin J.} and Jeffrey Travers and Michael Otto and Naohiro Inohara and Gabriel N{\'u}{\~n}ez",
year = "2013",
doi = "10.1038/nature12655",
language = "English",
volume = "503",
pages = "397--401",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7476",

}

TY - JOUR

T1 - Staphylococcus δ-toxin induces allergic skin disease by activating mast cells

AU - Nakamura, Yuumi

AU - Oscherwitz, Jon

AU - Cease, Kemp B.

AU - Chan, Susana M.

AU - Muñoz-Planillo, Raul

AU - Hasegawa, Mizuho

AU - Villaruz, Amer E.

AU - Cheung, Gordon Y C

AU - McGavin, Martin J.

AU - Travers, Jeffrey

AU - Otto, Michael

AU - Inohara, Naohiro

AU - Núñez, Gabriel

PY - 2013

Y1 - 2013

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84888023947&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84888023947&partnerID=8YFLogxK

U2 - 10.1038/nature12655

DO - 10.1038/nature12655

M3 - Article

VL - 503

SP - 397

EP - 401

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7476

ER -