Accumulating epidemiologic evidence has revealed that metabolic syndrome is an independent risk factor for psoriasis development and is associated with more severe psoriasis. Adiponectin, primarily recognized as a metabolic mediator of insulin sensitivity, has been newly drawing attention as a mediator of immune responses. Here we demonstrate that adiponectin regulates skin inflammation, especially IL-17-related psoriasiform dermatitis. Mice with adiponectin deficiency show severe psoriasiform skin inflammation with enhanced infiltration of IL-17-producing dermal Vg4 þ gd-T cells. Adiponectin directly acts on murine dermal gd-T cells to suppress IL-17 synthesis via AdipoR1. We furthermore demonstrate here that the adiponectin level of skin tissue as well as subcutaneous fat is decreased in psoriasis patients. IL-17 production from human CD4-or CD8-positive T cells is also suppressed by adiponectin. Our data provide a regulatory role of adiponectin in skin inflammation, which would imply a mechanism underlying the relationship between psoriasis and metabolic disorders.

Psoriasis is a chronic inflammatory skin disease characterized by scaly indurated erythema. It impairs patients’ quality of life enormously. It has been recognized not only as a skin disease but as a systemic disease, since it also causes arthritis (psoriatic arthritis) and mental disorders. Furthermore, an association with cardiovascular events is indicated. With the advent of biologics, treatment of psoriasis dramatically changed due to its high efficacy and tolerable safety. A variety of biologic agents are available for the treatment of psoriasis nowadays. However, characteristics such as rapidity of onset, long-term efficacy, safety profile, and effects on comorbidities are different. Better understanding of those characteristic leads to the right choice for individual patients, resulting in higher persistence, longer drug survival, higher patient satisfaction, and minimizing the disease impact of psoriasis. In this paper, we focus on the efficacy and safety profile of biologics in psoriasis patients, including plaque psoriasis and psoriatic arthritis. In addition, we discuss the impact of biologics on comorbidities caused by psoriasis.

Purpose: Both patients with cutaneous T-cell lymphoma (CTCL) and those with atopic dermatitis (AD) have pruritus, T H 2-biased T cells, and a tendency to have bacterial infections, suggesting a common pathologic basis for these two diseases. Recently, interleukin (IL)-22-producing T cells were reported in skin of patients with AD. In this study, we investigated expression levels of T H 22-and T H 17-related molecules in lesional skin and sera isolated from patients with CTCL.Experimental Design: Skin biopsies and sera were collected from patients with CTCL or psoriasis and from healthy volunteers. Protein and mRNA expression levels of IL-22, IL-17A, IL-17F, IL-23p19, IL-10, IL-4, CCL20, CCR6, IL-8, and IL-20 were examined in lesional tissue and a subset of these molecules in sera. Phosphorylation of STAT3 was also assessed in lesional skin of CTCL and psoriasis by immunohistochemistry.Results: IL-22, IL-10, IL-4, CCL20, and CCR6 mRNA and protein levels, but not IL-17A, IL-17F, IL-23p19, IL-8, or IL-20, were significantly elevated in lesional skin of CTCL. Phosphorylation of STAT3 was detected in epidermis of CTCL skin. Moreover, serum IL-22, IL-10, and CCL20 levels were increased in CTCL and correlated with disease severity.Conclusions: Our results suggest that IL-22 is important in establishing the tumor microenvironment for CTCL. Enhanced expression of CCL20 may explain epidermal hyperplasia and migration of CCR6 þ cells, such as Langerhans cells, into lesional skin. Relatively low expression of IL-17 may explain the lack of neutrophils in lesions of CTCL, which correlates with bacterial infections that commonly occur in skin affected by CTCL. Clin Cancer Res; 17(24); 7529-38. Ó2011 AACR.

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The advent of biologics brought a paradigm shift in ways to treat psoriatic patients because they have dramatic efficacy. At the same time, safety concerns about biologics have been raised. In this paper, we focus on the safety profile of biologics for psoriasis. As of 2017, six biologics are available in Japan. Two tumor necrosis factor-a inhibitors; infliximab and adalimumab, one anti-interleukin (IL)-12/23p40 antibody; ustekinumab, and IL-17 inhibitors; secukinumab, ixekizumab and brodalumab. Secukinumab and ixekizumab are anti-IL-17A antibodies. Brodalumab is an anti-IL17RA antibody. In this review, we pick up topics which have drawn attention regarding the safety of biologics and discuss them with recent published work.

Gout occurs in individuals with hyperuricemia when monosodium urate (MSU) crystals precipitate in tissues and induce acute inflammation via phagocytic cells such as monocytes. MSU crystals have been demonstrated in skin diseases such as tophaceous gout or psoriasis; however, the importance of MSU crystals in the skin is totally unknown. In this study, we found that MSU crystals, through P2Y6 receptors, stimulated normal human keratinocytes (NHK) to produce IL-1α, IL-8/CXCL8, and IL-6. P2Y6 receptor expression increased in MSU-stimulated NHK. Both P2Y6-specific antagonist and P2Y6 antisense oligonucleotides significantly inhibited the production of IL-1α, IL-8/CXCL8, and IL-6 by NHK. Similarly, the P2Y6-specific antagonist completely inhibited the MSU-induced production of IL-1β by THP-1 cells, a human monocytic cell line. Remarkably, the P2Y6-specific antagonist significantly reduced neutrophil influx in both mouse air pouch and peritonitis models. Thus, these results indicate that the P2Y6 receptor signaling pathway may be a potential therapeutic target for MSU-associated inflammatory diseases, such as tophaceous gout.

Psoriasis is an inflammatory cutaneous disorder characterized by marked epidermal thickening and Th1 and Th17 cell infiltration. At present, the contribution of B cells to the pathogenesis of psoriasis is unclear. In mice, topical application of imiquimod induces inflamed skin lesions and serves as an experimental animal model for human psoriasis. In this study, we showed that imiquimod-induced skin inflammation was more severe in CD19(-/-) than WT mice. These inflammatory responses were negatively regulated by a unique IL-10-producing CD1d(hi)CD5(+) regulatory B cell subset (B10 cells) that was absent in CD19(-/-) mice and represented only 1-2% of splenic B220(+) cells in WT mice. Splenic B10 cells entered the circulation and migrated to draining LNs during imiquimod-induced skin inflammation, thereby suppressing IFN-γ and IL-17 production. Furthermore, adoptive transfer of these B10 cells from WT mice reduced inflammation in CD19(-/-) mice. The present findings provide direct evidence that B10 cells regulate imiquimod-induced skin inflammation and offer insights into regulatory B cell-based therapies for the treatment of psoriasis.

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