Skin exposure to pathogenic bacteria such as Staphylococcus aureus is associated with exacerbation of atopic dermatitis, an inflammatory skin disease affecting approximately 20% of children and 5% of adults in the U.S. The mechanisms by which the S. aureus induces skin inflammation are thought to involve the activation of many different proinflammatory responses. In contrast to this prevailing view, we set out to determine whether there was a predominant mechanism by which S. aureus induced skin inflammation by using an in vivo mouse model of epicutaneous S. aureus exposure. We uncovered a previously unrecognized essential mechanism by which S. aureus skin exposure induced skin inflammation that involved IL-36 cytokine responses. IL-36 cytokines, including IL-36?, IL-36? and IL-36?, are recently identified members of the IL-1 cytokine family. They are expressed by keratinocytes and have been implicated in the pathogenesis of psoriasis through the induction of IL-17-producing T cells. However, a role for the S. aureus in triggering IL-36 responses has not been reported and thus represents an unexpected mechanism by which the host responds to bacteria on the skin surface to promote cutaneous inflammation. Very little is known about the regulation of IL-36 cytokines, including whether IL-36 cytokines are induced by bacterial virulence factors or host pattern recognition receptors and how IL-36 cytokines regulate T cell responses. Therefore, our central hypothesis is that epicutaneous S. aureus exposure activates keratinocytes to produce IL-36 cytokines (via S. aureus virulence factors and host pattern recognition receptors) that drive skin inflammation by inducing T cell-mediated IL-17 responses.
In Aim 1, we will test the hypothesis that IL-36 cytokines are produced by keratinocytes during epicutaneous S. aureus exposure in response to bacterial virulence factors and/or host pattern recognition receptors.
In Aim 2, we will test the hypothesis that IL-36-induced IL-17-producing ?? T cells and Th17 cells differentially contribute to S. aureus-induced skin inflammation.
In Aim 3, we will test the hypothesis that human keratinocytes produce IL 36 cytokines that induce human ?? and CD4+ T cells to promote skin inflammation in response to S. aureus. To translate our findings to human skin, we will use an in vivo humanized mouse model that possesses matched human grafted skin and human immune cells from the same donors, which is innovative approach to study both human keratinocyte and T cell responses in vivo. Taken together, this proposal will uncover novel mechanisms involving IL-36 responses that promote skin inflammation induced by pathogenic S. aureus bacteria on the surface of the skin. The insights gained in this proposal will provide new mechanisms to target for future immunotherapies to inhibit skin inflammation in atopic dermatitis and potentially other inflammatory skin diseases.

Public Health Relevance

Staphylococcus aureus skin colonization is associated with flares of atopic dermatitis, which is an important human inflammatory skin disease that affects 15-30% of children and 5% of adults and results in $5.2 billion in annual healthcare costs in the U.S. Although the prevailing view is that S. aureus skin exposure induces many different proinflammatory responses to contribute to skin inflammation, this proposal will focus on a previously unrecognized and predominant role for IL-36 responses in mediating the S. aureus-induced skin inflammation. This proposal is highly significant because it will provide novel insights into how pathogenic bacteria on the surface of the skin promote skin inflammation as well as specific immune mechanisms to target therapeutically in atopic dermatitis and potentially other inflammatory skin diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Cibotti, Ricardo
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Johns Hopkins University
Schools of Medicine
United States
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Archer, Nathan K; Jo, Jay-Hyun; Lee, Steven K et al. (2018) Injury, dysbiosis, and filaggrin deficiency drive skin inflammation through keratinocyte IL-1? release. J Allergy Clin Immunol :
Thompson, John M; Miller, Robert J; Ashbaugh, Alyssa G et al. (2018) Mouse model of Gram-negative prosthetic joint infection reveals therapeutic targets. JCI Insight 3: