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

Seitaro Nakagawa; Masanori Matsumoto; Yuki Katayama; Rena Oguma; Seiichiro Wakabayashi; Tyler Nygaard; Shinobu Saijo; Naohiro Inohara; Michael Otto; Hiroyuki Matsue; Gabriel Núñez; Yuumi Nakamura

doi:10.1016/j.chom.2017.10.008

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

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

Authors

Affiliations

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: [email protected].
⁷ Department of Dermatology, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan. Electronic address: [email protected].

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.

MeSH terms

Alarmins / drug effects*
Animals
Bacterial Proteins / metabolism
Bacterial Toxins / pharmacology*
Cytokines / metabolism
Dermatitis / immunology
Dermatitis / metabolism
Dermatitis / microbiology
Disease Models, Animal
Female
Humans
Inflammation / immunology*
Inflammation / pathology
Interleukin-1 / metabolism
Interleukin-17 / metabolism*
Interleukin-1alpha / metabolism
Keratinocytes / drug effects*
Keratinocytes / immunology*
Keratinocytes / microbiology
Keratinocytes / pathology
Mice
Mice, Inbred C57BL
Myeloid Differentiation Factor 88 / metabolism
Neutrophils / metabolism
Peptides / pharmacology
Receptors, Interleukin-1
Staphylococcal Skin Infections / immunology*
Staphylococcal Skin Infections / microbiology
Staphylococcal Skin Infections / pathology
Staphylococcus aureus / pathogenicity*
T-Lymphocytes / metabolism
Trans-Activators / metabolism
Virulence

Substances

Agr protein, Staphylococcus aureus
Alarmins
Bacterial Proteins
Bacterial Toxins
Cytokines
Interleukin-1
Interleukin-17
Interleukin-1alpha
Myd88 protein, mouse
Myeloid Differentiation Factor 88
Peptides
Receptors, Interleukin-1
Trans-Activators
interleukin 1F6, mouse
interleukin-36 receptor, mouse
staphylococcal delta toxin

Abstract

MeSH terms

Substances

Grants and funding