User:Immcarle1/sandbox

I want to describe the mechanism of IL-17 in psoriasis development.

Psoriasis
Recent work suggests the IL-23/IL-17 pathway plays a major role in the autoimmune disorder psoriasis. In this condition immune cells react to inflammatory molecules released within the skin around the joints and scalp. This response causes the epidermal cells to recycle more rapidly than usual, which leads to the formation of red, scaly lesions and chronic skin inflammation. Studies conducted in mice demonstrate that removing either IL-23 or IL-17 negatively impacts the progression of psoriasis. Mice injected with monoclonal antibodies targeting IL-17 blocked, or neutralized, down stream signaling of this cytokine and decreased epidermal hyperplasia. Similarly, genetically modifying mice to not express IL-23 or IL-17 receptors significantly reduced psoriatic lesion development upon stimulation with tumor promoter 12-O-tetradecanoylphorbol-13-acetate.

Analysis using RT-PCR showed an enrichment of both IL-17 and its inducing cytokine IL-23 in biopsies taken from lesion versus non-lesion skin of psoriasis patients. Visualization of psoriatic lesions with immunostaining showed an abundance of cells containing IL-17. The traditional Th17 cells as well as neutrophils and cytotoxic T cells containing IL-17 were localized within the psoriatic lesion. Additionally, immunostaining showed a high number of dendritic cells containing the stimulatory IL-23. These results indicate an excessive infiltration of proinflammatory immune cells and IL-17 are associated with the development of psoriasis.

IL-17 promotes psoriasis by contributing to the inflammatory response that damages and overturns the keratinocyte cells of the epidermal layer. Inflammation begins with keratinocyte cells entering the final stages of their cell cycle, which activates immature dendritic cells (DC). Cytokines released from DCs stimulate dying keratinocytes to secrete TNF-alpha, IL-1 and IL-6 leading to the chemotaxis of T cells, natural killer cells and monocytes to the epidermis. These cells release IL-23 which induces the Th17 cells to produce IL-17.

IL-17 interaction with IL-17RA receptors abundant on the keratinocyte cell surface incite the epidermal cells to increase expression of additional IL-6, antimicrobial peptides, IL-8, ICAM-1 and CCL20. Increased concentration of IL-6 alters the epidermal environment by decreasing the ability of T regulatory cells to control the behavior of Th17 cells. Reduced regulation allows uninhibited proliferation of Th17 cells and production of IL-17 in psoriatic lesions augmenting IL-17 signaling. Antimicrobial peptides and IL-8 attract neutrophils to the site of injury where these cells degranulate upon and phagocytose the damaged and inflamed keratinocyte cells. Additionally, ICAM-1 assists in the adhesion of neutrophils to the epithelial surface and allows for entry of neutrophils from the bloodstream. New immature DCs are also recruited by CCL20 via chemotaxis where their activation restarts and amplifies the cycle of inflammation. IL-17 and additional cytokines released from the influx of neutrophils, T and dendritic cells mediate effects on localized leukocytes and keratinocytes that supports the progression of psoriasis by inciting chronic inflammation.