Psoriasis: what we have learned from mouse models

Abstract

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.

IL-37 Ameliorates the Inflammatory Process in Psoriasis by Suppressing Proinflammatory Cytokine Production

“…Serum IL-6 levels are significantly higher in patients with active psoriasis than in controls, and the levels correlate with disease severity of psoriatic arthritis (29,30). Upon stimulation of DCs in disease initiation, keratinocytes are activated to produce autologous IL-6 to occur the epidermal hyperproliferation and impaired differentiation, as demonstrated by the hyperkeratosis exhibited by another psoriasis model: keratin 14-IL-6 transgenic mice (11). In contrast, keratinocyte-derived IL-6 activates myeloid DCs to initiate communication between the DCs and T cells in adaptive immunity (10).…”

“…Psoriasis is one of the most common immune-mediated chronic inflammatory cutaneous disorders and is characterized by epidermal hyperplasia, dilated blood vessels, and increased leukocyte infiltration (10,11). Although the pathogenesis of this autoimmune disease has not been fully characterized, there is growing evidence that the formation and maintenance of psoriatic plaques are mediated by cell-cell interactions between resident skin cells (mainly keratinocytes) and elements of the immune system in the context of a combined Th1/Th17/Th22 immune response (12)(13)(14).…”

c-Jun, at the crossroad of the signaling network

“…Each AP-1 component exhibits unique cell type-and tissue-specific distribution (Wagner et al, 2010), but this can be modified by the cellular environment. A vast number of growth factors, cytokines, chemokines, hormones and environmental stresses have been shown to regulate AP-1 at the level of gene expression, mRNA turnover and protein stability, thereby affecting the relative abundance of AP-1 within the cells.…”

RAC1 in keratinocytes regulates crosstalk to immune cells by Arp2/3 dependent control of STAT1

“…The complex relationship between keratinocytes and immune cells makes it difficult to understand the etiology of chronic skin inflammations (Lowes et al, 2007;Wagner et al, 2010): do defects in keratinocyte barrier function or cytokine production by keratinocytes trigger activation of the immune system or is an abnormally activated immune system causing barrier defects and an altered cytokine profile of the keratinocytes?…”