GATA3 expression is decreased in psoriasis and during epidermal regeneration; induction by narrow-band UVB and IL-4.

Psoriasis is characterized by hyperproliferation of keratinocytes and by infiltration of activated Th1 and Th17 cells in the (epi)dermis. By expression microarray, we previously found the GATA3 transcription factor significantly downregulated in lesional psoriatic skin. Since GATA3 serves as a key switch in both epidermal and T helper cell differentiation, we investigated its function in psoriasis. Because psoriatic skin inflammation shares many characteristics of epidermal regeneration during wound healing, we also studied GATA3 expression under such conditions.Psoriatic lesional skin showed decreased GATA3 mRNA and protein expression compared to non-lesional skin. GATA3 expression was also markedly decreased in inflamed skin of mice with a psoriasiform dermatitis induced with imiquimod. Tape-stripping of non-lesional skin of patients with psoriasis, a standardized psoriasis-triggering and skin regeneration-inducing technique, reduced the expression of GATA3. In wounded skin of mice, low GATA3 mRNA and protein expression was detected. Taken together, GATA3 expression is downregulated under regenerative and inflammatory hyperproliferative skin conditions. GATA3 expression could be re-induced by successful narrow-band UVB treatment of both human psoriasis and imiquimod-induced psoriasiform dermatitis in mice. The prototypic Th2 cytokine IL-4 was the only cytokine capable of inducing GATA3 in skin explants from healthy donors. Based on these findings we argue that GATA3 serves as a key regulator in psoriatic inflammation, keratinocyte hyperproliferation and skin barrier dysfunction.

Effective treatment of psoriasis with narrow-band UVB phototherapy is linked to suppression of the IFN and Th17 pathways.

Narrow-band ultraviolet-B (NB-UVB) phototherapy is an effective treatment for psoriasis. The molecular mechanisms underlying its efficacy are incompletely understood. To identify NB-UVB-induced molecular pathways that may account for its anti-inflammatory efficacy, gene expression profiling was performed using epidermal RNA from lesional and nonlesional skin from patients with psoriasis undergoing NB-UVB therapy. Downregulation of Th17 signaling pathway was observed during NB-UVB therapy in psoriatic epidermis. Strong inhibition of the Th17 pathway by UVB was confirmed in an ex vivo organ culture system by demonstrating reduced signal transducer and activator of transcription 3 (STAT3) phosphorylation and ß-defensin-2 production. These results were further substantiated by demonstrating that NB-UVB inhibited the Th17-dependent psoriasis-like dermatitis in mice. Other pathways affected by NB-UVB therapy include the IFN signaling pathway, epidermal differentiation, and other well-known therapeutic targets in psoriasis, such as the glucocorticoid, vitamin D, peroxisome proliferator-activated receptor, and IL-4 signaling pathways. In conclusion, clinical improvement of psoriasis by NB-UVB is linked to suppression of Th17 and type I and type II IFN signaling pathways, which are critical in the pathogenesis of the disease. Our results show that clinically effective NB-UVB therapy is based on suppression of a broad range of important molecular pathways in psoriatic skin.

Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis.

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.

IFN-alpha enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis.

Keratinocytes play a key role in innate immune responses of the skin to bacterial and viral pathogens. Viral double-stranded RNA and its synthetic analogue polyriboinosinic-polyribocytidylic acid (poly-IC) are recognized via multiple pathways involving the receptors Toll-like receptor 3 (TLR3), protein kinase R (PKR), and the recently described cytosolic RNA helicases retinoic acid-inducible gene-I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). We show that preincubation of human keratinocytes with IFN-alpha enhances the proinflammatory responses to poly-IC. Kinetic studies suggest that this is mediated via upregulation of the receptors TLR3, PKR, RIG-I, and MDA5. Interestingly, expression of RIG-I, MDA5, and PKR was significantly increased in lesional skin from patients with psoriasis, a chronic inflammatory skin disease that is characterized by high IFN-alpha levels. These results suggest that psoriatic keratinocytes show increased sensitivity to viral RNA intermediates, thereby leading to excessive proinflammatory responses and maintenance of the inflammatory skin phenotype. Here, we provide early evidence that point toward a role for the recently described cytosolic innate RNA receptors in non-viral chronic inflammatory diseases.

Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice.

The non-obese diabetic (NOD) mouse is a widely used animal model for the study of human diabetes. The lymphocytic (peri-)insulitis is preceded by an early accumulation of dendritic cells (DC) around the islets of Langerhans. This DC accumulation is thought to derive from an influx of monocytes attracted by pro-inflammatory chemokines. Besides chemokines, extracellular matrix (ECM) proteins play an important role in the accumulation of leukocytes in tissues. We studied the expression of the chemokines CCL2, CCL5, CXCL10, CCL19 and CCL21 over time in pancreases of NOD and control mice by ELISA on pancreas lysates as well as by immunohistochemistry. In addition, we studied the adhesive capacity of bone marrow-derived DC (BMDC) to ECM components. DC in the NOD pancreas accumulated at sites with an intense expression of fibronectin. In vitro, NOD BMDC showed increased fibronectin adhesion and increased VLA-5 expression. At the time of early DC accumulation (<10 wk), the lymphoid tissue-related chemokines CCL19 and CCL21 were increased. Our findings support the view that the early accumulation of DC around the NOD islets is not the consequence of an enhanced attraction of precursors and immature DC by pro-inflammatory chemokines. It rather might be the consequence of an aberrantly enhanced adhesion and retention of NOD DC.