Psoriasis is a common skin inflammatory disorder known for its hallmark of having abnormal keratinocyte differentiation.  In psoriatic skin, the expression of liver X receptors (LXR𝛼 and LXR𝛽), a nuclear receptor family of transcription factors has shown to be down-regulated. In addition, LXR plays an integral part in the control of keratinocyte differentiation. However, very few studies have been conducted to understand the role of LXRs during skin inflammation. We hypothesized that LXRs in the skin can interfere the immune cascade in the induction of psoriatic inflammation. We first evaluated imiquimod (IMQ)-induced psoriatic inflammation in murine ear skin that was simultaneously treated with or without an LXR agonist (GW3965) for 11 days. We found that IMQ-induced skin inflammation was milder in mice treated with GW3965 than in mice treated with its vehicle. In addition, qPCR analysis demonstrated that the gene expression levels of pro-resolution mediators (ABCA1, MerTK and TGF-𝛽) in the IMQ-treated skin were higher in the LXR agonist-treated group than in the control group. We also performed lipidomics analysis to understand the role of the LXR agonist for the generation of lipid mediators in the skin. The levels of key immune recruitment lipid mediators (leukotriene D4 and prostaglandin E2) in the skin lesions were lower in the LXR agonist-treated group than in the control group. To further illustrate the role of LXRs for the immune cell recruitment in psoriatic skin inflammation, we performed whole mount skin imaging. We observed that neutrophil recruitment in the IMQ-treated skin were markedly lower in the LXR agonist-treated group compared to the control group. These results suggest that the activation of LXRs can alleviate psoriatic skin inflammation via the generation of pro-resolving molecules and regulation of the synthesis of lipid mediators.

Imiquimod-induced psoriatic inflammation can be attenuated by the application of a Liver X receptor agonist through the production of pro-resolution molecule