Systemic inflammation-induced adipose tissue remodeling drives psoriasis exacerbation in obesity through epigenetic and immunometabolic dysregulation

Obesity has been known to be associated with psoriasis, negatively affecting its prevalence, severity, and treatment response. However, a detailed systemic inflammatory microenvironment in obesity-associated psoriasis has not been extensively investigated. To explore this further, we used a mouse model of psoriasis induced by topical application of imiquimod or injection of IL-23. We found that obese mice exhibited systemic inflammatory responses when exposed to imiquimod, with increased expression of inflammatory cytokines in the skin and elevated serum levels of mediators implicated in psoriasis pathogenesis. Notably, imiquimod also caused a significant decrease in body weight and fat, which was more pronounced in obese mice, resulting a thinner subcutaneous fat layer. Further analysis revealed higher macrophage infiltration, upregulated genes relating to the inflammatory response, and increased expression of necrosis-associated molecules in the perigonadal fat of imiquimod-treated obese mice than in lean mice. IL-23 injection induced comparable pathogenic features of psoriatic inflammation in obese and lean mice without causing adipose tissue destruction or systemic increase of inflammatory mediators. Overall design: At 8 weeks of age, mice were divided into two groups and were fed either a high-fat diet (HFD) or a standard chow diet for a duration of 12 weeks. Throughout the study, both groups of mice underwent daily topical applications of 62.5 mg of IMQ cream (5%) (Aldara™) on their shaved backs for five consecutive days. Additionally, to induce intradermal IL-23-induced psoriatic skin inflammation, the mice received daily injections of 1 µg of rmIL-23 in PBS at a specified location on their shaved backs for five days.