Clinical and Molecular Effects of Interleukin-17 Pathway Blockade in Psoriasis

February 2020 | Volume 19 | Issue 2 | Original Article | 138 | Copyright © February 2020

Published online January 17, 2020

Lawrence Green , Jeffrey M. Weinberg , Alan Menter , Jennifer Soung , Edward Lain , Abby Jacobson

aGeorge Washington University School of Medicine, Washington, DC bIcahn School of Medicine at Mount Sinai, New York, NY cBaylor Scott & White, Dallas, TX dSouthern California Dermatology, Santa Ana, CA eAustin Institute for Clinical Research, Pflugerville, TX fOrtho Dermatologics, Bridgewater, NJ

however, has demonstrated that pathogenic T cells producing high levels of IL-17 in response to IL-23 play a central role in the pathogenesis of psoriasis.10 Activation of native immune cells results in production of proinflammatory cytokines (eg, TNFα and interferon-α), which stimulate myeloid dermal dendritic cells to produce IL-12 and IL-23.3,9 These cytokines induce activation of T cells and differentiation into Th17 and Th1 cells, with greater differentiation into the Th17 lineage in the presence of IL-23.9,11 Th17 cells produce IL-17A, IL-17F, IL-21, IL-22, and TNFα.3 In addition to Th17-propagated cytokines, other ligands of the IL-17 receptor implicated in the proinflammatory cascade include IL-17C and IL-17E.11,12

Keratinocytes stimulated by IL-17 ligands result in aberrant differentiation and proliferation that promote the production of proinflammatory chemokines, characterized by a self-amplifying inflammatory response.13 IL-17A recruits immune cells to psoriatic lesions by enhancing keratinocyte chemokine expression, including chemokine (C-C motif) ligand 20 (which mediates recruitment of myeloid dendritic cells and Th17 cells) and chemokine (C-X-C motif) ligand 1 (CXCL1), CXCL3, CXCL5, CXCL6, and CXCL8 (which drive neutrophil recruitment), thus perpetuating the inflammatory process.14,15 IL-17A also downregulates the expression of filaggrin, which binds to keratin fibers in epithelial cells, supporting the disruption of skin barrier function.3 Neutrophils, mast cells, and Tc17 cells, all of which are found in psoriatic lesions, also produce IL-17A.16

IL-17C–stimulated endothelial cells lead to increased TNFα, and IL-17C/TNFα–stimulated keratinocytes have similar inflammatory gene response patterns as those induced by IL-17A/TNFα, contributing to a positive proinflammatory feedback loop between endothelial cells and the epidermis.17 IL-17A, IL-17C, and TNFα additively and synergistically amplify the proinflammatory effects of one another.11 IL-17E, also known as IL-25, signals via the IL-17 receptor A and IL-17 receptor B subunits and is overexpressed in keratinocytes located within psoriatic plaques.12 Keratinocyte-derived IL-17E has been implicated in plaque formation and hyperproliferation. IL-17E–mediated macrophage activation leads to enhanced inflammation through recruitment of immune cells, including monocytes and neutrophils.18

Rationale for Targeting the IL-17 Pathway in Psoriasis
The IL-17 family of cytokines interact with the transmembrane receptors (IL-17 receptors A, B, C, D, and E).14 These IL-17 receptors are expressed on keratinocytes, dendritic cells, and a variety of immune cells and mediate response to IL-17 cytokines. 15 IL-17A, IL-17F, and the IL-17A/F heterodimer share the same IL-17 receptor for signaling, resulting in downstream gene activation and proinflammatory activity.16,19 IL-17C is also present in psoriatic lesions, localizing in keratinocytes, endothelial cells, and leukocytes, and is the most abundant IL-17 cytokine in psoriatic skin.17 The effects of IL-17C on TNFα production and synergistic actions are similar to those of IL-17A, and the specific IL-17 receptor it interacts with shares a subunit (IL-17 receptor A) in common with that of IL-17A, IL-17F, and IL-17A/F.14,15,17,19 Messenger RNA levels (Figure 1) and protein levels of IL-17A, IL-17F, and IL-17C are highly upregulated in psoriatic skin.20 Additionally, IL-17E has been shown to be produced at elevated levels in keratinocytes located within psoriatic plaques, further supporting the role of IL-17 cytokines in the immunopathologic mechanisms of psoriasis.12 IL-17 receptor A expression, however, is no different among nonlesional and lesional psoriatic skin.20 Furthermore, increased levels of both Th17 cells and IL-17 have been found in the blood as well as skin lesions in patients with psoriasis.21,22 A proposed pathobiologic model of psoriasis suggests that a self-sustaining feedback loop is established, in which production of IL-17 in psoriasis pathogenesis leads to aberrant skin cell differentiation and proliferation (Figure 2).11 Through the proinflammatory feedback mechanisms described previously, chronic activation of IL-17 signaling ultimately leads to the signs and symptoms of psoriasis.16 Inhibition of the IL-17 Pathway in Psoriasis The central role of IL-17 in the pathogenesis of psoriasis makes it an attractive therapeutic target, and there are multiple approaches to inhibition of IL-17–mediated signaling. Mechanisms of action involve direct antagonism of IL-17 as well as indirect, upstream approaches.23-25 Currently, 3 approved agents affect the IL-17 pathway directly, either by binding to the IL-17A ligand (secukinumab and ixekizumab) or by binding to IL-17 receptor A (brodalumab).21,26 Brodalumab is a fully human anti–IL-17 receptor A monoclonal antibody that binds IL-17 receptor A with high affinity and prevents the signaling of multiple cytokines involved in psoriasis (IL-17A, IL-17F, IL-17A/F, and IL-17E [IL-25]).21,27 Brodalumab undergoes selective, direct binding to IL-17 receptor A, resulting in inhibition of the induction of multiple downstream inflammatory factors (Figure 3).11,25,27,28 In contrast to brodalumab, secukinumab and ixekizumab target IL-17A, an IL-17 cytokine isoform that propagates inflammation