Staphylococcus aureus Epicutaneous Exposure Drives Skin Inflammation via IL-36-Mediated T Cell Responses

Abstract

SUMMARY Staphylococcus aureus colonization contributes to skin inflammation in diseases such as atopic dermatitis, but the signaling pathways involved are unclear. Herein, epicutaneous S. aureus exposure to mouse skin promoted MyD88-dependent skin inflammation initiated by IL-36 but not IL-1α/β, IL-18 or IL-33. By contrast, an intradermal S. aureus challenge promoted MyD88-dependent host defense initiated by IL-1β rather than IL-36, suggesting that different IL-1 cytokines trigger MyD88-signaling depending on the anatomical depth of S. aureus cutaneous exposure. The bacterial virulence factor PSMα but not α-toxin or δ-toxin contributed to the skin inflammation, which was driven by IL-17-producing γδ and CD4+ T cells via direct IL-36R-signaling in the T cells. Finally, adoptive transfer of IL-36R-expressing T cells to IL-36R-deficient mice was sufficient for mediating S. aureus-induced skin inflammation. Together, this study defines a previously unknown pathway by which S. aureus epicutaneous exposure promotes skin inflammation involving IL-36R/MyD88-dependent IL-17 T cell responses.

Skin microbiota–host interactions

“…S. aureus is a versatile pathogen with a broad array of virulence factors 81,82 , including neutrophil-killing toxins 83 , chemotaxis inhibitors 84 , anti-phagocytic and anti-killing surface molecules 57,85–88 , superantigens, and immune evasion proteins 89,90 . In patients with atopic dermatitis, S. aureus isolates grow as biofilms on the skin and produce proteases that degrade host AMPs, such as cathelicidin LL-37 91 .…”

Staphylococcus aureus: Master Manipulator of the Skin

“…The Nakagawa et al (2017) study shows that PSMα from S. aureus activates keratinocyte production of IL-1α and IL-36α and this in turn stimulates γδ T cells and innate lymphoid cell type 3 (ILC3)-mediated IL-17 release as well as neutrophil recruitment. Similarly, the Liu et al (2017) study shows that PSMα can induce keratinocyte IL-36α to stimulate IL-17-producing γδ T cells and CD4 + T cells. Interestingly, only application of S. aureus on the skin surface produced this response while subcutaneous injections of S. aureus promoted a distinct IL-1β response.…”

“…Two papers in this issue of Cell Host & Microbe by Nakagawa et al (2017) and Liu et al (2017) define a pathway by which epicutaneous Staphylococcus aureus promotes skin inflammation and may contribute to AD. …”

“…In this issue of Cell Host & Microbe , two papers by Nakagawa et al (2017) and Liu et al (2017) have further outlined pathways through which the epicutaneous application of S. aureus can induce an AD-like phenotype on murine skin (Nakagawa et al, 2017; Liu et al, 2017). The Nakagawa et al (2017) study shows that PSMα from S. aureus activates keratinocyte production of IL-1α and IL-36α and this in turn stimulates γδ T cells and innate lymphoid cell type 3 (ILC3)-mediated IL-17 release as well as neutrophil recruitment.…”

“…Our group has observed that an S. aureus protease null strain failed to penetrate into the deeper layers of the skin and also failed to induce T H 2 cytokine production in mice (Nakatsuji et al, 2016). Interestingly, this penetration of S. aureus into the skin may be linked to the differences Liu et al (2017) observed in subcutaneous versus epicutaenous S. aureus infections. Furthermore, we have shown that a secreted S. aureus factor(s) can stimulate human keratinocytes to increase expression of epithelial serine proteases that further damage the skin barrier (Williams et al, 2017).…”