# REDD1 dissociates the therapeutic and adverse effects of glucocorticoids in skin

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2021 · $482,817

## Abstract

Glucocorticoids (Gcs) are among the most effective and frequently used anti-inflammatory drugs for different
chronic inflammatory skin diseases including atopic dermatitis and psoriasis. Unfortunately, chronic
glucocorticoids induce multiple deleterious side effects including skin atrophy. Thus, there is significant unmet
need for novel safer glucocorticoid receptor (GR) – targeted anti-inflammatory therapies. GR is a transcription
factor that regulates gene expression via (i) transactivation that requires GR binding as a homodimer to
glucocorticoid-responsive elements in gene promoters and (ii) transrepression that is chiefly mediated via
negative interaction between GR and other transcription factors including anti-inflammatory factors AP-1 and
NF-kB. Transrepression by GR is an important mechanism for anti-inflammatory effects of glucocorticoids. In
contrast, GR transactivation often mediates steroid adverse effects. The molecular mechanisms of steroid-
induced skin atrophy, the major side effect of topical steroids, are poorly understood. We found that
glucocorticoids activated the expression of REDD1 (regulated in development and DNA damage response), a
stress-inducible inhibitor of mTOR, in mouse and human skin. REDD1 knockout (KO) animals are partially
resistant to glucocorticoid-induced epidermal and subcutaneous adipose atrophy, which correlated with the
protection of CD34+ follicular epithelial stem cells as well as p63+ keratinocyte progenitors in REDD1 KO
epidermis during chronic steroid treatment. At the same time, the lack of REDD1 did not affect anti-
inflammatory effect of glucocorticoids as evaluated by ear edema test. Expression profiling revealed that ~
70% of glucocorticoid receptor (GR) target genes activated in WT epidermis and related to lipid and protein
metabolism were not activated in epidermis of REDD1 KOs, however, the negative effect of glucocorticoids on
inflammatory gene expression was very similar in both genotypes. Overall, our findings reveal a novel feed
forward pathway in GR activation by its target gene/protein REDD1; and established atrophogenic role of
REDD1 in steroid-treated skin. The overarching goal of this proposal is to test our hypothesis that REDD1
inhibitors would significantly reduce skin atrophy caused by topical glucocorticoids. We propose to further
explore the role of REDD1 in skin inflammation using chronic murine models of dermatitis; to determine the
effect of REDD1 on major steps in GR activation; and to seek for pharmacological inhibitors among FDA-
approved and experimental drugs using bioinformatics approach. This highly innovative program will strongly
impact our understanding of major catabolic/anabolic pathways in skin and the results could be advantageous
for the skin diseases as well as for various visceral inflammatory diseases treated by glucocorticoids as they
induce atrophy in numerous tissues including muscle and bone.

## Key facts

- **NIH application ID:** 10114189
- **Project number:** 5R01AI125366-05
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Irina Budunova
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $482,817
- **Award type:** 5
- **Project period:** 2017-03-22 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114189

## Citation

> US National Institutes of Health, RePORTER application 10114189, REDD1 dissociates the therapeutic and adverse effects of glucocorticoids in skin (5R01AI125366-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10114189. Licensed CC0.

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