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.
Glucocorticoids remain the most commonly used anti-inflammatory drugs in dermatology, however, their use is limited by the development of side effects, particularly skin atrophy. We discovered that REDD1 is causatively involved in skin atrophy. The proposed studies will test the novel concept of safe anti-inflammatory therapy in which glucocorticoids are combined with REDD1 inhibitors.
|Baida, Gleb; Bhalla, Pankaj; Yemelyanov, Alexander et al. (2018) Deletion of the glucocorticoid receptor chaperone FKBP51 prevents glucocorticoid-induced skin atrophy. Oncotarget 9:34772-34783|