# IL-36 responses in Staphylococcus aureus driven skin inflammation

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $359,700

## Abstract

Project Summary / Abstract
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-36α, IL-36β and IL-36γ, 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 γδ 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 γδ 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.

## Key facts

- **NIH application ID:** 9899816
- **Project number:** 5R01AR073665-03
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** Nathan K. Archer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $359,700
- **Award type:** 5
- **Project period:** 2018-04-09 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899816

## Citation

> US National Institutes of Health, RePORTER application 9899816, IL-36 responses in Staphylococcus aureus driven skin inflammation (5R01AR073665-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899816. Licensed CC0.

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