# Targeting keratinocyte cholesterol metabolism to reveal novel mechanisms for treating inflammatory skin disease

> **NIH NIH F31** · NORTHWESTERN UNIVERSITY · 2022 · $46,752

## Abstract

PROJECT SUMMARY
Inflammation is involved in an abundant number of acute and chronic skin pathologies, which together contribute
to high patient and healthcare burden. Topical immunosuppressants such as topical corticosteroids are first-line
treatments despite their association with a myriad of adverse effects such as skin atrophy, striae, and rosacea,
among others. Further, while many inflammatory skin conditions involve similar pathways of immune activation
and disease progression, the development of targeted anti-inflammatory therapies would aid in delineating our
understanding of the shared and unique molecular mechanisms that accompany inflammation in the skin.
Cholesterol is integral to the normal functioning of skin and recently, excess intracellular cholesterol has been
associated with inflammatory activation by interleukin-17A (IL-17A) in cultured keratinocytes. Interestingly, these
findings resemble the cholesterol-dependent inflammatory processes found in activated macrophages,
suggesting keratinocytes could be subjected to similar mechanisms of cholesterol regulation in the setting of
inflammation. Therefore, research is required to delineate the relationship between cholesterol metabolism and
keratinocyte-induced inflammation. Our lab pioneered a synthetic high-density lipoprotein-like nanoparticle (HDL
NP) capable of modulating cellular cholesterol through specifically binding to scavenger receptor class B type 1
(SR-B1), a transporter responsible for cellular cholesterol flux. Application of HDL NPs in the skin is attractive
due to the well-established presence of SR-B1 in the epidermis and the favorable physical properties of HDL
NPs that may enable keratinocyte targeting and localization to all layers of the epidermis. Further, topical HDL
NP administration in wounded corneal epithelial cells has demonstrated anti-inflammatory benefit, further
supporting a link between cholesterol modulation and immune activation. We aim to use HDL NPs as a powerful
tool to mechanistically study how changes in cholesterol metabolism affect inflammation in the skin. Our
overarching hypothesis is the following: keratinocyte cholesterol levels control inflammatory signaling in the skin.
In the first aim of the study, we will understand how HDL NP modulates keratinocyte cholesterol in the setting of
IL-17A activation. In the second aim, we will investigate IL-17A-dependent inflammatory signaling in
keratinocytes with a particular focus in measuring the expression of chemoattractants that are known to
perpetuate skin inflammation. In the final aim of the study, we will investigate the therapeutic potential of targeting
cholesterol modulation in vivo using the imiquimod-induced psoriasis-like mouse model as a model of skin
inflammation. Project success will better delineate the role of cholesterol metabolism in inflammatory
skin disease to develop novel topical therapies to reduce inflammation.

## Key facts

- **NIH application ID:** 10537802
- **Project number:** 1F31AR081685-01
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Jacquelyn Trujillo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10537802

## Citation

> US National Institutes of Health, RePORTER application 10537802, Targeting keratinocyte cholesterol metabolism to reveal novel mechanisms for treating inflammatory skin disease (1F31AR081685-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10537802. Licensed CC0.

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