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Cell Host Microbe. 2017 Nov 8;22(5):667-677.e5. doi: 10.1016/j.chom.2017.10.008.

Staphylococcus aureus Virulent PSMα Peptides Induce Keratinocyte Alarmin Release to Orchestrate IL-17-Dependent Skin Inflammation.

Author information

1
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan.
2
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
3
Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
4
Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA.
5
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan; Division of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba 260-8673, Japan.
6
Department of Pathology and Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Electronic address: gabriel.nunez@umich.edu.
7
Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. Electronic address: yumi01@chiba-u.jp.

Abstract

Staphylococcus aureus commonly colonizes the epidermis, but the mechanisms by which the host senses virulent, but not commensal, S. aureus to trigger inflammation remain unclear. Using a murine epicutaneous infection model, we found that S. aureus-expressed phenol-soluble modulin (PSM)α, a group of secreted virulence peptides, is required to trigger cutaneous inflammation. PSMα induces the release of keratinocyte IL-1α and IL-36α, and signaling via IL-1R and IL-36R was required for induction of the pro-inflammatory cytokine IL-17. The levels of released IL-1α and IL-36α, as well as IL-17 production by γδ T cells and ILC3 and neutrophil infiltration to the site of infection, were greatly reduced in mice with total or keratinocyte-specific deletion of the IL-1R and IL-36R signaling adaptor Myd88. Further, Il17a-/-f-/- mice showed blunted S. aureus-induced inflammation. Thus, keratinocyte Myd88 signaling in response to S. aureus PSMα drives an IL-17-mediated skin inflammatory response to epicutaneous S. aureus infection.

KEYWORDS:

Agr virulence; IL-1; IL-36; Myd88; PSMs; S. aureus; alarmins; pathogen virulence; skin infection

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PMID:
29120744
PMCID:
PMC5728420
DOI:
10.1016/j.chom.2017.10.008
[Indexed for MEDLINE]
Free PMC Article

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