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

ABSTRACT: 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-1?/?, IL-18, or IL-33. By contrast, an intradermal S. aureus challenge promoted MyD88-dependent host defense initiated by IL-1? 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 PSM?, but not ?-toxin or ?-toxin, contributed to the skin inflammation, which was driven by IL-17-producing ?? 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.

SUBMITTER: Liu H

PROVIDER: S-EPMC5774218 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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

Liu Haiyun H Archer Nathan K NK Dillen Carly A CA Wang Yu Y Ashbaugh Alyssa G AG Ortines Roger V RV Kao Tracy T Lee Steven K SK Cai Shuting S SS Miller Robert J RJ Marchitto Mark C MC Zhang Emily E Riggins Daniel P DP Plaut Roger D RD Stibitz Scott S Geha Raif S RS Miller Lloyd S LS

Cell host & microbe 20171101 5

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 depe ...[more]

PMID: 29120743

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Project description:In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.

Dataset Information

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

Publications

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

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