Serum Metabolomic Profiling Reveals the Amelioration Effect of Methotrexate on Imiquimod-Induced Psoriasis in Mouse

Metabolites are building blocks of cellular function. These species are involved in enzyme-catalyzed chemical reactions and are essential for cellular function. Upstream biological disruptions result in a series of metabolomic changes, and as such the metabolome holds a wealth of information that is thought to be most predictive of phenotype. Uncovering this knowledge is a work in progress. The field of metabolomics is still maturing; the community has leveraged proteomics experience when applicable and developed a range of sample preparation and instrument methodology along with myriad data processing and analysis approaches. Research focuses have now shifted toward a fundamental understanding of the biology responsible for metabolomic changes. There are several types of metabolomics experiments including both targeted and untargeted analyses. While untargeted, hypothesis generating, workflows exhibit many valuable attributes, challenges inherent to the approach remain. This Critical Insight comments on these challenges, focusing on the identification process of LC-MS based untargeted metabolomics studies – specifically in mammalian systems. Biological interpretation of metabolomics data hinges on the ability to accurately identify metabolites. The range of confidence associated with identifications that is often overlooked is reviewed, and opportunities for advancing the metabolomics field are described.

The worldwide incidence and prevalence of psoriasis is poorly understood. To better understand this, we performed a systematic review of published population-based studies on the incidence and prevalence of psoriasis. Three electronic databases were searched from their inception dates to July 2011. A total of 385 papers were critically appraised; 53 studies reported on the prevalence and incidence of psoriasis in the general population. The prevalence in children ranged from 0% (Taiwan) to 2.1% (Italy), and in adults it varied from 0.91% (United States) to 8.5% (Norway). In children, the incidence estimate reported (United States) was 40.8/100,000 person-years. In adults, it varied from 78.9/100,000 person-years (United States) to 230/100,000 person-years (Italy). The data indicated that the occurrence of psoriasis varied according to age and geographic region, being more frequent in countries more distant from the equator. Prevalence estimates also varied in relation to demographic characteristics in that studies confined to adults reported higher estimates of psoriasis compared with those involving all age groups. Studies on the prevalence and incidence of psoriasis have contributed to a better understanding of the burden of the disease. However, further research is required to fill existing gaps in understanding the epidemiology of psoriasis and trends in incidence over time.

Topical application of imiquimod (IMQ), a TLR7/8 ligand and potent immune activator, can induce and exacerbate psoriasis, a chronic inflammatory skin disorder. Recently, a crucial role was proposed for the IL-23/IL-17 axis in psoriasis. We hypothesized that IMQ-induced dermatitis in mice can serve as a model for the analysis of pathogenic mechanisms in psoriasis-like dermatitis and assessed its IL-23/IL-17 axis dependency. Daily application of IMQ on mouse back skin induced inflamed scaly skin lesions resembling plaque type psoriasis. These lesions showed increased epidermal proliferation, abnormal differentiation, epidermal accumulation of neutrophils in microabcesses, neoangiogenesis, and infiltrates consisting of CD4(+) T cells, CD11c(+) dendritic cells, and plasmacytoid dendritic cells. IMQ induced epidermal expression of IL-23, IL-17A, and IL-17F, as well as an increase in splenic Th17 cells. IMQ-induced dermatitis was partially dependent on the presence of T cells, whereas disease development was almost completely blocked in mice deficient for IL-23 or the IL-17 receptor, demonstrating a pivotal role of the IL-23/IL-17 axis. In conclusion, the sole application of the innate TLR7/8 ligand IMQ rapidly induces a dermatitis closely resembling human psoriasis, critically dependent on the IL-23/IL-17 axis. This rapid and convenient model allows further elucidation of pathogenic mechanisms and evaluation of new therapies in psoriasis.