Psoriasis is a common heterogeneous inflammatory skin disease with a complex pathophysiology and limited treatment options. Here we performed proteomic analyses of human psoriatic epidermis and found S100A8-S100A9, also called calprotectin, as the most upregulated proteins, followed by the complement component C3. Both S100A8-S100A9 and C3 are specifically expressed in lesional psoriatic skin. S100A9 is shown here to function as a chromatin component modulating C3 expression in mouse and human cells by binding to a region upstream of the C3 start site. When S100A9 was genetically deleted in mouse models of skin inflammation, the psoriasis-like skin disease and inflammation were strongly attenuated, with a mild immune infiltrate and decreased amounts of C3. In addition, inhibition of C3 in the mouse model strongly reduced the inflammatory skin disease. Thus, S100A8-S100A9 can regulate C3 at the nuclear level and present potential new therapeutic targets for psoriasis.

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Inflammation is a physiological response of the body to tissue injury, pathogen invasion and irritants. In the course of inflammation, immune cells of the innate and/or adaptive immune system are activated and recruited to the site of inflammation. Attraction and activation of immune cells is regulated by a variety of different cytokines and chemokines, which are predominantly regulated by transcription factors such as AP-1, NF-κB, NFATs and STATs. The evidence that Jun/AP-1 proteins control inflammation in the skin is summarised in this article. Genetic mouse models have demonstrated that a loss of Jun/AP-1 expression in epidermal cells controls cytokine expression through transcriptional and post-transcriptional pathways. The absence of JunB in epithelial K5-expressing tissues leads to a multiorgan disease, which is characterised by increased levels of granulocyte colony-stimulating factor and interleukin 6. Deletion of both JunB and c-Jun, in a constitutive or inducible manner, leads to perinatal death of newborn pups and to a psoriasis-like disease in adults, in which tumour necrosis factor α and the TIMP-3/TACE pathway have central roles. The loss or reduction of Jun expression in the epidermis relieves a block on cytokine expression. As a consequence, the increased levels of cytokines in mice lead to diseases reminiscent of psoriasis and systemic lupus erythematosus in human patients. New targets identified in mouse models, together with investigations on human samples, will provide important new avenues for therapeutic interventions in psoriasis and other inflammatory skin diseases.

Psoriasis is a common inflammatory skin disease of unknown etiology, for which there is no cure. This heterogeneous, cutaneous, inflammatory disorder is clinically characterized by prominent epidermal hyperplasia and a distinct inflammatory infiltrate. Crosstalk between immunocytes and keratinocytes, which results in the production of cytokines, chemokines and growth factors, is thought to mediate the disease. Given that psoriasis is only observed in humans, numerous genetic approaches to model the disease in mice have been undertaken. In this Review, we describe and critically assess the mouse models and transplantation experiments that have contributed to the discovery of novel disease-relevant pathways in psoriasis. Research performed using improved mouse models, combined with studies employing human cells, xenografts and patient material, will be key to our understanding of why such distinctive patterns of inflammation develop in patients with psoriasis. Indeed, a combination of genetic and immunological investigations will be necessary to develop both improved drugs for the treatment of psoriasis and novel curative strategies.

Psoriasis is a common inflammatory skin disease with limited treatment options that is characterized by a complex interplay between keratinocytes, immune cells, and inflammatory mediators. MicroRNAs (miRNAs) are regulators of gene expression and play critical roles in many human diseases. A number of miRNAs have been described to be up-regulated in psoriasis, but their causal contribution to disease development has not been demonstrated. We confirm that miR-21 expression is increased in epidermal lesions of patients with psoriasis and that this leads to reduced epidermal TIMP-3 (tissue inhibitor of matrix metalloproteinase 3) expression and activation of TACE (tumor necrosis factor-α-converting enzyme)/ADAM17 (a disintegrin and metalloproteinase 17). Using patient-derived skin samples and mouse models of psoriasis, we demonstrate that increased miR-21 may be a consequence of impaired transcriptional activity of Jun/activating protein 1 (AP-1), leading to activation of the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (Stat3) pathway. Inhibition of miR-21 by locked nucleic acid (LNA)-modified anti-miR-21 compounds ameliorated disease pathology in patient-derived psoriatic skin xenotransplants in mice and in a psoriasis-like mouse model. Targeting miR-21 may represent a potential therapeutic option for the treatment of psoriasis.

Squamous cell carcinomas (SCCs) are highly heterogeneous tumours, resulting from deranged expression of genes involved in squamous cell differentiation. Here we report that microRNA‐34a (miR‐34a) functions as a novel node in the squamous cell differentiation network, with SIRT6 as a critical target. miR‐34a expression increases with keratinocyte differentiation, while it is suppressed in skin and oral SCCs, SCC cell lines, and aberrantly differentiating primary human keratinocytes (HKCs). Expression of this miRNA is restored in SCC cells, in parallel with differentiation, by reversion of genomic DNA methylation or wild‐type p53 expression. In normal HKCs, the pro‐differentiation effects of increased p53 activity or UVB exposure are miR‐34a‐dependent, and increased miR‐34a levels are sufficient to induce differentiation of these cells both in vitro and in vivo. SIRT6, a sirtuin family member not previously connected with miR‐34a function, is a direct target of this miRNA in HKCs, and SIRT6 down‐modulation is sufficient to reproduce the miR‐34a pro‐differentiation effects. The findings are of likely biological significance, as SIRT6 is oppositely expressed to miR‐34a in normal keratinocytes and keratinocyte‐derived tumours.

Inducible epidermal deletion of JunB and c-Jun in adult mice causes a psoriasis-like inflammatory skin disease. Increased levels of the proinflammatory cytokine TNFα play a major role in this phenotype. Here we define the underlying molecular mechanism using genetic mouse models. We show that Jun proteins control TNFα shedding in the epidermis by direct transcriptional activation of tissue inhibitor of metalloproteinase-3 (TIMP-3), an inhibitor of the TNFα-converting enzyme (TACE). TIMP-3 is down-regulated and TACE activity is specifically increased, leading to massive, cell-autonomous TNFα shedding upon loss of both JunB and c-Jun. Consequently, a prominent TNFα-dependent cytokine cascade is initiated in the epidermis, inducing severe skin inflammation and perinatal death of newborns from exhaustion of energy reservoirs such as glycogen and lipids. Importantly, this metabolic “cachectic” phenotype can be genetically rescued in a TNFR1-deficient background or by epidermis-specific re-expression of TIMP-3. These findings reveal that Jun proteins are essential physiological regulators of TNFα shedding by controlling the TIMP-3/TACE pathway. This novel mechanism describing how Jun proteins control skin inflammation offers potential targets for the treatment of skin pathologies associated with increased TNFα levels.

cTransforming growth factor ␤1 (TGF-␤1) is a pleiotropic factor involved in the regulation of extracellular matrix (ECM) synthesis and remodeling. In search for novel genes mediating the action of TGF-␤1 on vascular ECM, we identified the member of the lysyl oxidase family of matrix-remodeling enzymes, lysyl oxidase-like 4 (LOXL4), as a direct target of TGF-␤1 in aortic endothelial cells, and we dissected the molecular mechanism of its induction. Deletion mapping and mutagenesis analysis of the LOXL4 promoter demonstrated the absolute requirement of a distal enhancer containing an activator protein 1 (AP-1) site and a Smad binding element for TGF-␤1 to induce LOXL4 expression. Functional cooperation between Smad proteins and the AP-1 complex composed of JunB/Fra2 accounted for the action of TGF-␤1, which involved the extracellular signal-regulated kinase (ERK)-dependent phosphorylation of Fra2. We furthermore provide evidence that LOXL4 was extracellularly secreted and significantly contributed to ECM deposition and assembly. These results suggest that TGF-␤1-dependent expression of LOXL4 plays a role in vascular ECM homeostasis, contributing to vascular processes associated with ECM remodeling and fibrosis.