Cutaneous Liver X Receptor Activation Prevents the Formation of Imiquimod-Induced Psoriatic Dermatitis

Abstract

Psoriasis is a chronic inflammatory skin disorder characterized by keratinocyte (KC) hyperproliferation ( Nestle et al., 2009 Nestle F.O. Kaplan D.H. Barker J. Psoriasis. N Engl J Med. 2009; 361: 496-509 Google Scholar ). In recent years, psoriasis is recognized as an immunometabolic disease associate with multiorgan abnormalities and dyslipidemia ( Sterry et al., 2007 Sterry W. Strober B.E. Menter A. International Psoriasis CouncilObesity in psoriasis: the metabolic, clinical and therapeutic implications. Report of an interdisciplinary conference and review. Br J Dermatol. 2007; 157: 649-655 Google Scholar ); however, it remains unclear whether the dysregulation of lipid metabolism in the skin affects the pathogenesis of psoriasis. Liver X receptor (LXR) is a nuclear receptor composed of two isoforms: LXRα (NR1H3) and LXRβ (NR1H2) ( Chawla et al., 2001 Chawla A. Repa J.J. Evans R.M. Mangelsdorf D.J. Nuclear receptors and lipid physiology: opening the X-files. Science. 2001; 294: 1866-1870 Google Scholar ), which are important regulators of cholesterol ( Schulman, 2017 Schulman I.G. Liver X receptors link lipid metabolism and inflammation. FEBS Lett. 2017; 591: 2978-2991 Google Scholar ). Previous studies showed that the topical application of LXR agonists inhibits the development of contact dermatitis ( Fowler et al., 2003 Fowler A.J. Sheu M.Y. Schmuth M. Kao J. Fluhr J.W. Rhein L. et al. Liver X receptor activators display anti-inflammatory activity in irritant and allergic contact dermatitis models: liver-X-receptor-specific inhibition of inflammation and primary cytokine production. J Invest Dermatol. 2003; 120: 246-255 Google Scholar ) and that LXRα expression is suppressed in KCs in psoriatic lesions ( Gupta et al., 2010 Gupta D.S. Kaul D. Kanwar A.J. Parsad D. Psoriasis: crucial role of LXR-alpha RNomics. Genes Immun. 2010; 11: 37-44 Google Scholar ). In this study, we investigated the role of LXR signaling in psoriasis through topical application of a synthetic LXR agonist, GW3965, in an imiquimod (IMQ)-induced psoriatic murine model.