The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses

Abstract

Psoriasis is a complex inflammatory process resulting from activation of the well-defined interleukin (IL)-23/T17 cytokine axis. We review the role of key cytokines IL-17 and IL-23 in psoriasis, as well as tumor necrosis factor (TNF)α, focusing on therapeutic cytokine interventions and what they reveal about psoriatic inflammation. The potential role of recently described epidermal IL-36RN and CARD14 genetic mutations in psoriasis pathogenesis is also explored, because they augment keratinocyte responses to proinflammatory cytokines. The discovery of these genetic mutations in familial and pustular psoriasis suggests new links between cytokine-induced gene products and IL-1 family members from keratinocytes, which may regulate features of the disease, including epidermal hyperplasia and neutrophil infiltrating responses.

Figure 1. Essential cells and molecules in the pathogenesis of psoriasis lesions

The IL-23-IL-17 axis is well understood in psoriasis. Inflammatory and resident myeloid DCs become activated to produce IL-23. This drives production of IL-17 ligands (IL-17A, IL-17F) from αβ and γδ T cells (T17), and IL-22 by subsets of CD4⁺ (Th22) and CD8⁺ (Tc22) cells, while IL-12 drives production of IFNγ. These T-cell derived cytokines can then activate the epidermis to produce further inflammatory chemokines and cytokines. Some will recruit cells into the skin: IL-8, CXCL1, 2 & 3 are all neutrophil chemotaxins; CCL20 attracts CCR6⁺ DCs and T17 cells; and VEGF is important in inducing the vascular hyperplasia seen in psoriasis. Others such as IL-19, IL-20, and IL-22 induce epidermal hyperplasia, while IL-17C is a keratinocyte produced IL-17 ligand. There is synergy (green S) between IL-17 and TNFα, as well as between IL-17 and IL-22. Chemokines for inflammatory DCs (immune triggers) such as CCL20 may help initiate lesions. There are abundant IL-36 cytokines in psoriasis, which are also involved in neutrophil chemotaxis, and IL-36Ra is the natural antagonist for this effect. Mutations in the IL-36Ra gene lead to the runaway inflammation seen in familial pustular psoriasis. Mutations in epidermal CARD14 (mCARD14) in familial psoriasis may increase endogenous activation in response to a trigger, inducing abundant cytokine and chemokine production (such as IL-8, CCL20, IL-36). Wild-type CARD14 may also play a role in initiating and amplifying the psoriatic process. LL37 complexed with nucleic acids can activate DCs. When established, over 4000 transcripts are dysregulated in psoriasis, undoubtedly with other interactive circuits that are not diagramed here. * T cells bearing γδ TCR may be less inhibited by IFNγ [90].

Figure 2. Histological responses of psoriasis lesions to IL-17 blockade

Hematoxylin and eosin sections (upper panel) and keratin 16 (K16, lower panel) during early phase clinical trials with (a) brodalumab (AMG 827), and (b) Ixekizumab (LY2439821) at baseline non-leisonal (NL), lesional (LS), and week 6 (WK 6). NL skin showed some K16 staining around a hair follicule (left) There was resolution of the histological changes of psoriasis as well as decreased keratin 16 (K16) staining. Size bar is 100μm. Reprinted with permission from the original publications ([references 40] and [38]).