REDD1/DDIT4 knockout prevents skin atrophy in aged mice

Summary: Abstract Body: Glucocorticoids (GCs) are the drugs of choice for treating inflammatory skin diseases in the elderly, and their use is expected to increase, despite their well-known side effects, including skin atrophy. In previous studies, we identified that mTOR inhibitor REDD1/DDIT4 plays a causative role in steroid-induced atrophy in young mice and showed that REDD1 knockout (KO) and pharmacological inhibition of REDD1 protected young mice against GC-induced skin thinning. However, the role of REDD1 in GCs-induced atrophy in aged skin is not known. We observed that chronic fluocinolone acetonide (FA) treatment in 20-month-old REDD1 KO mice induced epidermal hyperplasia, in contrast to significant epidermal thinning in WT isogenic controls. Transcriptomic analysis of FA-induced changes (2 µg, 24 h) revealed a much lower number of differentially expressed genes (DEGs; fold change > 2, p < 0.01) in 2-month-old REDD1 KO compared to WT males (550 vs. 1178), but in aged WT and REGG1 KO males the total number of DEGs was similar. Glucocorticoid receptor (GR) target genes involved in metabolic GC effects were induced, and genes related to proliferation and cell cycle regulation were downregulated regardless of age/genotype. Interestingly, in aged REDD1 KO mice the changes in transcriptome were shifted towards transrepression: 76% of GEGs were downregulated and the magnitude of downregulation was significantly higher than in WT animals. Gene set enrichment analysis (GSEA) identified a significant number of histone genes, including targets of Polycomb Repressive Complex 2 (PRC2) methylation, only in aged REDD1 KO mice. These findings suggest that the absence of REDD1 gene may reverse the phenotypic skin changes associated with GC-induced atrophy in aged mice, possibly through modulation of epigenetic pathways altered during intrinsic aging. Anna Klopot¹, Dominik Nowakowski², Gleb Baida³, Dimitri Trubetskoy³, Irina V. Budunova³ 1. Uniwersytet Medyczny im Piastow Slaskich we Wroclawiu Wydzial Lekarski, Wroclaw, Lower Silesian Voivodeship, Poland. 2. Department of Biostatistics and Medical Informatics, Uniwersytet Medyczny w Bialymstoku, Bialystok, Podlaskie Voivodeship, Poland. 3. Department of Dermatology, Northwestern University, Chicago, IL, United States. Translational Studies: Cell and Molecular Biology