Publication Date:
2013-11-01
Description:
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 delta-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by delta-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 delta-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of delta-toxin. Skin colonization with S. aureus, but not a mutant deficient in delta-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by delta-toxin was abrogated in Kit(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify delta-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090780/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4090780/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Nakamura, Yuumi -- Oscherwitz, Jon -- Cease, Kemp B -- Chan, Susana M -- Munoz-Planillo, Raul -- Hasegawa, Mizuho -- Villaruz, Amer E -- Cheung, Gordon Y C -- McGavin, Martin J -- Travers, Jeffrey B -- Otto, Michael -- Inohara, Naohiro -- Nunez, Gabriel -- R01 AR059688/AR/NIAMS NIH HHS/ -- R01AR059688/AR/NIAMS NIH HHS/ -- R01HL062996/HL/NHLBI NIH HHS/ -- Intramural NIH HHS/ -- England -- Nature. 2013 Nov 21;503(7476):397-401. doi: 10.1038/nature12655. Epub 2013 Oct 30.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan 48109, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24172897" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Bacterial Toxins/*metabolism/pharmacology
;
Calcium Signaling/drug effects
;
*Cell Degranulation/drug effects
;
Culture Media, Conditioned/pharmacology
;
Dermatitis, Atopic/immunology/metabolism/*microbiology/pathology
;
Female
;
Immunoglobulin E/biosynthesis/immunology
;
Inflammation/immunology/metabolism/microbiology/pathology
;
Interleukin-4/immunology
;
Intracellular Signaling Peptides and Proteins/metabolism
;
Male
;
Mast Cells/*cytology/drug effects
;
Mice
;
Phosphatidylinositol 3-Kinases/metabolism
;
Protein-Tyrosine Kinases/metabolism
;
Proto-Oncogene Proteins c-kit/genetics/metabolism
;
Staphylococcus aureus/metabolism/*pathogenicity
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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