IL-23 Versus IL-17 in the Pathogenesis of Psoriasis: There Is More to the Story Than IL-17A

August 2019 | Volume 18 | Issue 8 | Supplement Individual Articles | 202 | Copyright © August 2019

April W. Armstrong MD MPH,ª Charlotte Read MBBS BSc,ª Craig L. Leonardi MD,b Leon H. Kircik MDc

aDepartment of Dermatology, University of Southern California Keck School of Medicine, Los Angeles, CA bSaint Louis University School of Medicine, Saint Louis, MO; Central Dermatology Saint Louis, MO cIcahn School of Medicine at Mount Sinai, NY; Indiana Medical Center, Indianapolis, IN; Physicians Skin Care, PLLC; Skin Sciences, PLLC; DermResearch, PLLC, Louisville, KY

Abstract
Our understanding of psoriasis pathogenesis has evolved considerably. Cytokines within the TH1 and TH17 pathways have been found to be critical in psoriasis immunopathology. The TH17 pathway, which is centered around the interplay between IL-23 and IL-17, is now known to be at the core of psoriasis immune dysregulation. IL-23 acts as a key regulator of the TH17 pathway. Therapies targeting either IL-23 or IL-17 have shown great efficacy in psoriasis and have helped augment our understanding of psoriasis pathogenesis. Therapies such as ustekinumab and guselkumab inhibit IL-23. Ustekinumab targets the p40 subunit common to both IL-23 and IL-12 while guselkumab targets the p19 subunit found in IL-23. IL-17 subtypes trigger downstream inflammation in psoriasis. In particular, IL-17A, IL-17F, and IL-17C are elevated in psoriatic lesions; with IL-17F and IL-17C more elevated than IL-17A. Therapies such as secukinumab, ixekizumab, and brodalumab inhibit IL-17 subtypes. For example, brodalumab inhibits the downstream effects of all five IL-17 subtypes (IL-17A, IL-17AF, IL-17F, IL-17C, and IL-17E) via IL-17 receptor blockade; brodalumab can also normalize the levels of IL-23. Therefore, using a receptor-blocking therapy, such as brodalumab, that can act on multiple inflammatory cytokines, both IL-17 and IL-23 can be suppressed.

In this paper, we describe the importance of the TH17 pathway in psoriasis pathogenesis with a focus on the roles of IL-23 and IL-17 within this pathway. We also discuss the different IL-17 subtypes involved in psoriasis immunopathology and the multitude of cells that can produce these subtypes. Finally, we examine treatments that inhibit IL-23 and IL-17.

J Drugs Dermatol. 2019;18(8 Suppl 2):s202-208.

INTRODUCTION

Our understanding of psoriasis pathogenesis has evolved over time. Before the 1980s, psoriasis was viewed as a skin-limited disease and the therapeutic mechanisms of commonly used treatments were not well understood.1,2 When cyclosporine was found to improve psoriasis in transplant patients, researchers and clinicians began to appreciate the importance of the immune system in psoriasis pathogenesis.1–3 In the 1980s, researchers discovered that inhibition of tumor necrosis factor alpha (TNF-α) led to significant improvements in psoriasis.4 This initiated the development of multiple medications that target TNF-α. By the early 2000s, interleukin (IL)-17 was believed to play an essential role in psoriasis pathogenesis after IL-17 inhibition resulted in complete or near complete psoriasis clearance.5–8 Additionally, the efficacy of ustekinumab and other IL-23-specific therapies led to our appreciation that IL-23 has a critical role as a key regulator in psoriasis pathogenesis.

Thus, three cytokines, TNF-α, IL-23, and IL-17, have been instrumental in expanding our understanding of psoriasis pathogenesis and in developing efficacious psoriasis therapies. Below, we discuss in detail psoriasis pathogenesis, with a focus on the roles of IL-23 and IL-17 and therapies that target these two cytokines.

Overview of Pathogenesis of Psoriasis:
TH1 and TH17 Pathways Psoriasis occurs secondary to a complex interplay between the innate and adaptive immune systems, with the adaptive immune system performing a critical role.9 In psoriasis, dendritic cells secrete IL-12 and IL-23 cytokines.2,9 IL-12 stimulates naive T cells to differentiate into TH1 cells (Figure 1).2 The key cytokines of the TH1 pathway include interferon gamma (IFN-γ) and TNF-α (Figure 1).2 TNF-α plays several roles in the inflammatory cascade of psoriasis, including stimulating the infiltration of inflammatory cells into lesional skin, augmenting keratinocyte proliferation, and activating dendritic cells and TH17 cells.10–12 The TH17 pathway is central to psoriasis pathogenesis. Following IL-23 stimulation of naive T cells, TH17 cells secrete a number of inflammatory cytokines including IL-17, a key cytokine in psoriasis pathogenesis. A complex network of interactions between IL-23, IL-17, and other TH17 cell secreted molecules characterizes the TH17 pathway in what is known as the “IL-23/IL-17 axis”.13–18 This axis plays a critical role in psoriasis disease initiation and perpetuation, triggering a cascade of inflammatory molecules that lead to vasodilatation and angiogenesis.19,20 These vascular changes result in the skin thickening and erythema characteristic of plaque psoriasis.1