Pathophysiology of psoriasis: A review.

Psoriasis is a complex chronic inflammatory skin disease caused by the dynamic interplay between multiple genetic risk foci, environmental risk factors, and excessive immunological abnormalities. Psoriasis affects approximately 2% of the population worldwide, and dramatic advances have been achieved in the understanding and treatment options for psoriasis. Recent progress in biological therapies has revealed the fundamental roles of tumor necrosis factor-α, interleukin (IL)-23p19, and the IL-17A axis together with skin-resident immune cells and major signal transduction pathways in the pathogenesis of psoriasis. In addition to IL-17-producing T helper17 cells, innate lymphoid cell (ILC)3 induces psoriasis rashes directly without T-cell/antigen interaction in response to the released antimicrobial peptides from activated keratinocytes and inflammatory cytokines. ILC3 typically expresses retinoic acid receptor-related orphan receptor gamma t in the nucleus, matures in the presence of IL-7 and IL-23, and produces IL-17 and IL-22. The number of ILC3s is increased in the blood, psoriasis rash, and even in nonrash areas of psoriatic skin. Psoriasis is significantly associated with cardiovascular disease, metabolic syndrome, and inflammatory disorders, particularly the severe type. The similarity of enterobacteria in the psoriasis gut to that in diabetic patients may be related to its pathogenesis. In the current review, we focus on the pathophysiology of psoriasis in the accelerated immunological inflammatory loop, danger signal from keratinocytes, and cytokines, particularly IL-17 and IL-23p19. In addition, pathophysiological speculation with regard to morphology has been supplemented. Finally, the differences and similarities between psoriasis and atopic dermatitis are discussed.

ω3 fatty acid metabolite, 12-hydroxyeicosapentaenoic acid, alleviates contact hypersensitivity by downregulation of CXCL1 and CXCL2 gene expression in keratinocytes via retinoid X receptor α.

ω3 fatty acids show potent bioactivities via conversion into lipid mediators; therefore, metabolism of dietary lipids is a critical determinant in the properties of ω3 fatty acids in the control of allergic inflammatory diseases. However, metabolic progression of ω3 fatty acids in the skin and their roles in the regulation of skin inflammation remains to be clarified. In this study, we found that 12-hydroxyeicosapentaenoic acid (12-HEPE), which is a 12-lipoxygenase metabolite of eicosapentaenoic acid, was the prominent metabolite accumulated in the skin of mice fed ω3 fatty acid-rich linseed oil. Consistently, the gene expression levels of Alox12 and Alox12b, which encode proteins involved in the generation of 12-HEPE, were much higher in the skin than in the other tissues (eg, gut). We also found that the topical application of 12-HEPE inhibited the inflammation associated with contact hypersensitivity by inhibiting neutrophil infiltration into the skin. In human keratinocytes in vitro, 12-HEPE inhibited the expression of two genes encoding neutrophil chemoattractants, CXCL1 and CXCL2, via retinoid X receptor α. Together, the present results demonstrate that the metabolic progression of dietary ω3 fatty acids differs in different organs, and identify 12-HEPE as the dominant ω3 fatty acid metabolite in the skin.

Current understanding of the role of dietary lipids in the pathophysiology of psoriasis.

Dietary lipids are fundamental nutrients for human health. They are typically composed of various long-chain fatty acids which include saturated fatty acids (SFAs) and unsaturated fatty acids (UFAs). UFAs are further classified into several groups, such as omega-3 polyunsaturated fatty acids (PUFAs) and omega-6 PUFAs, depending on their chemical structure. Epidemiological studies have suggested the involvement of dietary lipids in the progression or regulation of psoriasis, a common chronic inflammatory skin disease induced via the IL-23/IL-17 axis. Although the underlying mechanisms by which dietary lipids regulate psoriasis have remained unclear, with the advancement of experimental techniques and the development of psoriasis mouse models, various possible mechanisms have been proposed. For example, SFAs may facilitate psoriatic dermatitis by causing activation of the inflammasome in keratinocytes and macrophages or by inducing IL-17-producing cells, such as Th17 and IL-17-producing γδ T cells in the skin, while omega-3 PUFAs may play inhibitory roles by suppressing Th17 differentiation. In this review, we summarize current data on the roles of dietary lipids in the development of psoriasis as revealed by mouse studies, and we discuss potential therapeutic strategies for psoriasis from the perspective of dietary lipids.

Resolvin E1 attenuates murine psoriatic dermatitis.

The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.

Basophils regulate the recruitment of eosinophils in a murine model of irritant contact dermatitis.

BACKGROUND: Although eosinophils have been detected in several human skin diseases in the vicinity of basophils, how eosinophils infiltrate the skin and the role of eosinophils in the development of skin inflammation have yet to be examined. OBJECTIVE: Using murine irritant contact dermatitis (ICD) as a model, we sought to clarify the roles of eosinophils in ICD and the underlying mechanism of eosinophil infiltration of the skin. METHODS: We induced croton oil-induced ICD in eosinophil-deficient ΔdblGATA mice with or without a reactive oxygen species (ROS) inhibitor. We performed cocultivation with fibroblasts and bone marrow-derived basophils and evaluated eosinophil migration using a chemotaxis assay. RESULTS: ICD responses were significantly attenuated in the absence of eosinophils or by treatment with the ROS inhibitor. ROS was produced abundantly by eosinophils, and both basophils and eosinophils were detected in human and murine ICD skin lesions. In coculture experiments, basophils attracted eosinophils, especially in the presence of fibroblasts. Moreover, basophils produced IL-4 and TNF-α in contact with fibroblasts and promoted the expression of eotaxin/CCL11 from fibroblasts in vitro. CONCLUSION: Eosinophils mediated the development of murine ICD, possibly through ROS production. Recruitment of eosinophils into the skin was induced by basophils in cooperation with fibroblasts. Our findings introduce the novel concept that basophils promote the recruitment of eosinophils into the skin through fibroblasts in the development of skin inflammation.