Pathophysiology of psoriasis: recent advances on IL-23 and Th17 cytokines

Abstract

T helper (Th) 17 cells, a novel T-cell subset, have been implicated in the pathogenesis of psoriasis and other autoimmune inflammatory diseases. Interleukin (IL)-23 stimulates survival and proliferation of Th17 cells, and thus serves as a key master cytokine regulator for these diseases. In psoriasis, IL-23 is overproduced by dendritic cells and keratinocytes, and this cytokine stimulates Th17 cells within dermis to make IL-17A and IL-22. IL-22, in particular, drives keratinocyte hyperproliferation in psoriasis. Future targeting of these key cytokines is likely to lead to dramatic clinical improvement in patients with psoriasis. This review focuses on the numerous recent studies on the roles of IL-23 and Th17 cells in the pathogenesis of psoriasis.

Figure 1

Schematic of the key cytokines and transcription factors involved in the differentiation, proliferation, and effector function of Th17 cells versus Th1 cells. Recent data indicate that IL-1 and not TGF-β1 is critical in the differentiation of naive T cells into Th17 in humans [9]. IFN—interferon; IL—interleukin; TGF—transforming growth factor; Th—T helper.

Figure 2

Sequence of events demonstrating the overall hypothesis that psoriasis is a Th17 disease. An initiating event such as trauma or skin surface microbes triggers IL-23 production by keratinocytes and resident dendritic cells, which in turn stimulates proliferation of CCR4⁺ and CCR6⁺ Th17 cells found within skin. These activated Th17 cells secrete Th17 cytokines including IL-22 and IL-17A, which cause keratinocyte growth and activation, respectively. Th17 cytokines also induce CCL20 production by keratinocytes, which fosters additional chemotaxis of CCR6⁺ Th17 cells and CCR6⁺ dendritic cells from blood into skin. Cytokines released by these newly recruited cells maintain psoriatic inflammation. IL—interleukin; Th—T helper.