Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

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Abstract

This review summarizes the steps from basic research on IL-17 family cytokines to understanding their role in psoriasis pathogenesis to the approval of a number of monoclonal antibodies targeting IL-17 pathways as first line treatment of psoriasis and psoriatic arthritis.

Abstract

The IL-17 cytokine family comprising IL-17A to IL-17F and receptor subunits IL-17RA to IL-17RE represents a genetically ancient intercellular network regulating local tissue homeostasis. Its pivotal role in antifungal defense and its central position in the pathogenesis of inflammatory diseases including psoriasis were discovered only relatively late in the early 2000s. Since the connection of dysregulated IL-17 and psoriasis pathogenesis turned out to be particularly evident, a number of monoclonal antibodies targeting IL-17 pathways have been approved and are used as first line treatment of moderate-to-severe plaque psoriasis and psoriatic arthritis, and further agents are currently in clinical development.

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Pathogenesis and therapy of psoriasis.

Michelle Lowes, Anne M Bowcock, James G. Krueger (2007)

Psoriasis is one of the most common human skin diseases and is considered to have key genetic underpinnings. It is characterized by excessive growth and aberrant differentiation of keratinocytes, but is fully reversible with appropriate therapy. The trigger of the keratinocyte response is thought to be activation of the cellular immune system, with T cells, dendritic cells and various immune-related cytokines and chemokines implicated in pathogenesis. The newest therapies for psoriasis target its immune components and may predict potential treatments for other inflammatory human diseases.

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IL-17 family cytokines and the expanding diversity of effector T cell lineages.

Casey T. Weaver, Robin Hatton, Paul R Mangan … (2007)

Since its conception two decades ago, the Th1-Th2 paradigm has provided a framework for understanding T cell biology and the interplay of innate and adaptive immunity. Naive T cells differentiate into effector T cells with enhanced functional potential for orchestrating pathogen clearance largely under the guidance of cytokines produced by cells of the innate immune system that have been activated by recognition of those pathogens. This secondary education of post-thymic T cells provides a mechanism for appropriately matching adaptive immunity to frontline cues of the innate immune system. Owing in part to the rapid identification of novel cytokines of the IL-17 and IL-12 families using database searches, the factors that specify differentiation of a new effector T cell lineage-Th17-have now been identified, providing a new arm of adaptive immunity and presenting a unifying model that can explain many heretofore confusing aspects of immune regulation, immune pathogenesis, and host defense.

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Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

Heather Conti, Fang-Fang Shen, Namrata Nayyar … (2009)

The commensal fungus Candida albicans causes oropharyngeal candidiasis (OPC; thrush) in settings of immunodeficiency. Although disseminated, vaginal, and oral candidiasis are all caused by C. albicans species, host defense against C. albicans varies by anatomical location. T helper 1 (Th1) cells have long been implicated in defense against candidiasis, whereas the role of Th17 cells remains controversial. IL-17 mediates inflammatory pathology in a gastric model of mucosal candidiasis, but is host protective in disseminated disease. Here, we directly compared Th1 and Th17 function in a model of OPC. Th17-deficient (IL-23p19−/−) and IL-17R–deficient (IL-17RA−/−) mice experienced severe OPC, whereas Th1-deficient (IL-12p35−/−) mice showed low fungal burdens and no overt disease. Neutrophil recruitment was impaired in IL-23p19−/− and IL-17RA−/−, but not IL-12−/−, mice, and TCR-αβ cells were more important than TCR-γδ cells. Surprisingly, mice deficient in the Th17 cytokine IL-22 were only mildly susceptible to OPC, indicating that IL-17 rather than IL-22 is vital in defense against oral candidiasis. Gene profiling of oral mucosal tissue showed strong induction of Th17 signature genes, including CXC chemokines and β defensin-3. Saliva from Th17-deficient, but not Th1-deficient, mice exhibited reduced candidacidal activity. Thus, the Th17 lineage, acting largely through IL-17, confers the dominant response to oral candidiasis through neutrophils and antimicrobial factors.

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Author and article information

Journal

Journal ID (nlm-ta): J Exp Med

Journal ID (iso-abbrev): J. Exp. Med

Journal ID (publisher-id): jem

Journal ID (hwp): jem

Title: The Journal of Experimental Medicine

Publisher: Rockefeller University Press

ISSN (Print): 0022-1007

ISSN (Electronic): 1540-9538

Publication date Collection: 06 January 2020

Publication date (Electronic): 14 November 2019

Volume: 217

Issue: 1

Electronic Location Identifier: e20191397

Affiliations

[1 ]Institute of Immunology, Hannover Medical School, Hannover, Germany

[2 ]Centre for Individualized Infection Medicine, Hannover, Germany

[3 ]Cluster of Excellence RESIST - Resolving Infection Susceptibility (EXC 2155), Hannover Medical School, Hannover, Germany

[4 ]Psoriasis Center at the Department of Dermatology and Comprehensive Center for Inflammation Medicine, University Medical Center Schleswig-Holstein, Campus Kiel, Germany

Author notes

Correspondence to Immo Prinz: prinz.immo@ 123456mh-hannover.de

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Immo Prinz https://orcid.org/0000-0002-8789-9578

Article

Publisher ID: 20191397

DOI: 10.1084/jem.20191397

PMC ID: 7037256

PubMed ID: 31727784

SO-VID: b0400c0d-ff86-4d58-90cd-4ebde9f463c8

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

History

Date received : 29 July 2019

Date revision received : 25 October 2019

Date accepted : 30 October 2019

Page count

Pages: 12

Funding

Funded by: Deutsche Forschungsgemeinschaft, DOI https://doi.org/10.13039/501100001659;

Interleukin-17 cytokines: Effectors and targets in psoriasis—A breakthrough in understanding and treatment

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Most cited references 110

Pathogenesis and therapy of psoriasis.

IL-17 family cytokines and the expanding diversity of effector T cell lineages.

Th17 cells and IL-17 receptor signaling are essential for mucosal host defense against oral candidiasis

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