373 Comparative analysis of acne and rosacea transcriptomes identifies compounds that target distinct disease-specific signatures of pathogenic inflammation and lipid biosynthesis

Abstract

Acne and rosacea are both prevalent inflammatory conditions with negative psychosocial impact and unmet clinical needs. Knowledge of distinct gene expression changes and implicated biologic pathways specific to acne versus rosacea is needed to streamline the selection of candidate compounds for rapid testing and development in the appropriate patient populations. We pooled and compared transcriptomes from N=12 acne patients, N=19 rosacea patients, and N=22 respective controls to obtain differentially expressed genes, then performed Ingenuity upstream regulator analysis to identify compounds highly predicted to target aberrantly regulated genes within each disease. We found that MAPK/ERK pathway inhibitors (SB203580, U0126), NFKB/IKK inhibitors (Bay 11-7082) and TNFα inhibitors (infliximab, etanercept) were predicted to downregulate inflammatory networks activated in both acne and rosacea. However, acne lesions featured higher levels of macrophage-secreted cytokines and neutrophil chemotactic factors that favored targeting by curcumin (P=1.6x10-10), omega-3 fatty acids/resolvin (P=1.4x10-8), flavonoid compounds (e.g. naringenin, P=7.5x10-6), and diphenyleneiodonium (P=7.8x10-4), while lymphocyte modulators targeting IFNγ and T cell chemoattraction had stronger predicted efficacy in rosacea. Strikingly, major regulators of lipid and sterol biosynthesis, including PPARA, PPARG, and SREBFs, were inhibited in acne lesions (Z= -4.86) and activated in rosacea (Z= +4.51), supporting distinct roles for PPAR agonists (thiazolidinediones, fibrates, pirinixic acid) as well as statin compounds in modulating respective disease states. Mechanism-driven assignment of candidate drugs for initial testing in either acne or rosacea will pave the way for rapid development of therapies with greatest efficacies for each condition.