Role of IL-17A in Psoriasis

The IL-17 family of cytokines contains six members: IL-17 (also known as IL-17A), IL-17B, IL-17C, IL-17D, IL-17E (also known as IL-25) and IL-17F. These cytokines consist of 163-202 amino acids with molecular masses of 20-30 kDa. They share four conserved cysteine residues at the C-terminal region that may participate in the formation of intermolecular disulfide linkages. IL-17A is the most extensively researched cytokine in this family. It is a disulfide-linked homodimeric glycoprotein which binds to and activates a heterodimeric transmembrane receptor complex consisting of IL-17RC and IL-17RA subunits. While IL-17A is linked to the pathogenesis of diverse autoimmune and inflammatory diseases, it also plays an essential role in host defense against extracellular bacteria and fungi.IL-17A has been implicated in the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), psoriasis and experimental autoimmune encephalomyelitis (EAE). Psoriasis is a chronic inflammatory skin disorder characterized by dermal hyperplasia. The key histological features of psoriatic skin are epidermal keratinocyte hyperproliferation, vascular proliferation and infiltration of dendritic cells, macrophages, neutrophils and T cells. Cells in psoriatic skin lesions are reported to have increased expression of IL-23, IL-22 and IL-17A. IL-17A has been shown to increase the expression of skin antimicrobial peptides including HBD-2, psoriasin (S100A7) and calprotectin (S100A8/9) in keratinocytes. This is in keeping with the observation that psoriasis patients are more resistant to skin infections than the general population, perhaps as a result of elevated antimicrobial peptide production. While IL-17F is also an inducer of antimicrobial genes in keratinocytes, it is not as potent as IL-17A.IL-17A has also been shown to increase the expression of a number of CXC chemokines such as CXCL-1, CXCL-3, CXCL-5 and IL-8. CXC chemokines are neutrophil attractants while CCL20 preferentially attracts memory T cells and dendritic cells. Thus, IL-17A contributes to the psoriatic condition by increasing the influx of neutrophils, dendritic cells and memory T cells into the psoriatic lesion.