The emerging role of IL-17 in the pathogenesis of psoriasis: preclinical and clinical findings

Abstract

Although the histological changes seen in psoriasis have long been well characterized, the underlying cellular and molecular mechanisms have only begun to be elucidated over the past 20 years. Proinflammatory factors such as tumor necrosis factor (TNF)-α have a central role in psoriasis pathogenesis, and many T-helper 1 (Th1) cytokines and messenger RNAs are elevated in psoriatic lesions. IL-17A, IL-17F, and other Th17 cell-derived cytokines have been shown in murine models to induce features that mimic human psoriasis. This review focuses on the emerging biology of the IL-17 cytokine family in psoriasis, and on the molecular and genetic information gained from animal models and human clinical studies that confirm IL-17 as a crucial proinflammatory cytokine in psoriasis. Expression of IL-17A, IL-17C, and IL-17F is strikingly increased in psoriatic lesions, and successful therapy is associated with restoration of the expression of a wide range of genes (including effector molecules downstream of IL-17 such as cytokines, chemokines, and antimicrobial peptides) to near-normal levels. Therapeutic agents in development that target IL-17 are discussed, and an emerging model of the key role of IL-17 in the pathogenesis of psoriasis is presented.

Figure 1

IL-17 family ligands and receptors. There are 6 well-defined IL-17 ligands and 5 receptors. The IL-17A, IL-17-F, and IL-17C ligands have elevated expression in psoriatic skin, and have their presumed major cellular sources in the skin highlighted, though other sources may contribute. Those 3 ligands, and IL-17E (IL-25), have demonstrated heteromeric receptor complexes, which in all cases include the IL-17 receptor A subunit, and 1 specific other IL-17 receptor subunit partner. Major cytoplasmic factors interacting with the IL-17 receptor complex are shown, as an example, for the IL-17RA/RC complex, where they are best studied. The IL-17A and IL-17F ligands form homo- and heterodimeric complexes. A dimeric state of the other ligands is illustrated by analogy, but has not been demonstrated, and the exact stoichiometries of the heteromeric receptor complexes are not fully determined. The ligand-receptor interactions are less well defined for IL-17B and IL-17D, and the requirement for an IL-17 receptor A subunit is unknown. IL-17=interleukin-17; IL-17R=IL-17 receptor; NF-κB=nuclear factor kappa B; NK(T)=natural killer (T) cells; Th17=T helper 17;

Figure 2

A model for the central role of IL-17 in psoriasis pathogenesis. This model includes core inflammatory elements that establish a self-reinforcing cycle, including Th17 skewing of naive T cells in the presence of IL-23 leading to the local production of IL-17 ligands. Keratinocytes in turn are stimulated by these IL-17 ligands leading to an aberrant differentiation program and elevated production of proinflammatory factors including AMPs and chemokines (including CCL20, which attracts both Th17 cells and DCs). These keratinocyte-derived factors in turn stimulate further recruitment of inflammatory cells, including IL-17 producing cells, and establish a self-sustaining inflammatory feedback loop. AMPs=antimicrobial peptides; DCs=dendritic cells; IL-12=interleukin-12; IL-17=interleukin-17; IL-23=interleukin-23; Th1=T helper 1; Th17=T helper 17; Th22=T helper 22.