Collection

Targeting IL-17 in inflammatory disease

The interleukin-17 (IL-17) family cytokines are strong inducers of inflammation and help to protect us against invading pathogens. However, they also have a dark side and contribute to the tissue destruction that occurs in chronic inflammatory and autoimmune diseases such as psoriasis, rheumatoid arthritis and multiple sclerosis.

The landmark discovery that IL-17-producing T cells were central drivers of these diseases positioned IL-17 as a promising therapeutic target. Several approaches that disrupt signalling by this cytokine family are now being tested in the clinic. Excitingly, real benefits for patients are starting to emerge, particularly for patients with psoriasis.

This collection of Research and Review-type articles highlights the role of the IL-17 pathway in inflammatory diseases, and how our improved understanding of the mechanisms of disease has revealed new opportunities for and potential benefits of IL-17-targeted therapies.

The content for this collection has been chosen by the editors of Nature Reviews Immunology and selected Comment and Review articles have been made freely available for 6 months, thanks to support from Eli Lilly and Company.

In addition, Nature Reviews Drug Discovery presents a Poster that summarizes the key aspects of the IL-17 pathway relevant to its potential as a therapeutic target, and an Animation of the immunopathology of psoriasis that illustrates how agents that target IL-17 signalling are being developed into novel therapies for this disease and other inflammatory conditions.

Comments and Reviews

  • Nature Reviews Drug Discovery | From the Analyst's Couch

    The IL-17–TH17 pathway is a popular target for the treatment of psoriasis and other autoimmune conditions. Bartlett and Million discuss the key agents in the pipeline, several of which are expected to gain approval in the near future.

    • Hilary S. Bartlett
    •  &  Ryan P. Million
  • Nature Reviews Immunology | Research Highlight

    MDR1 expression distinguishes pathogenic from non-pathogenic TH17 cells in humans.

    • Yvonne Bordon
  • Nature Medicine | Between Bedside and Bench

    Despite the irrefutable role of inflammation in psoriasis, a complete knowledge of what immune cells and cytokines are involved during initiation and progression of this skin disease is lacking. Moreover, the complexities of the immune cell network and potential differences between mice and humans have led to translational failures. It is therefore important that we acquire in-depth understanding of what inflammatory players, of the many involved, are crucial, if we wish to develop effective therapies. In 'Bedside to Bench', James Krueger discusses how a subset of T cells, TH17 cells, which release interleukin-17 in humans, seem to be essential for pathogenesis of psoriasis. The interplay between interleukin-17 and other cytokines that may potentially be involved in psoriasis also needs further investigation. Additionally, there are open questions as to what subset of T cells, other than TH17, also produce interleukin-17 and when. In 'Bench to Bedside', Burkhard Becher and Stanislav Pantelyushin examine this issue by looking at a mouse model of skin inflammation that resembles psoriasis in humans. A class of skin-invading innate immune cells called γδ T cells was shown to drive skin inflammation in this model, particularly during the early stages of the disease, suggesting that innate immunity plays an important part in the initiation of psoriasis.

    • Burkhard Becher
    •  &  Stanislav Pantelyushin
  • Nature Reviews Immunology | Review Article

    Immune homeostasis in the skin requires dynamic crosstalk between epithelial, stromal and immune cells, which is influenced by environmental insults and commensal microorganisms. Here, the authors highlight recent studies that provide an insight into the immunoregulatory mechanisms that mediate host defence and prevent chronic inflammation in the skin.

    • Manolis Pasparakis
    • , Ingo Haase
    •  &  Frank O. Nestle

Research

  • Nature | Letter

    A proof-of-concept phase I clinical trial demonstrates that targeting interleukin (IL)-23 with an antibody that binds to the p19 subunit leads to clinical improvement of disease in patients with moderate to severe psoriasis.

    • Tamara Kopp
    • , Elisabeth Riedl
    • , Christine Bangert
    • , Edward P. Bowman
    • , Elli Greisenegger
    • , Ann Horowitz
    • , Harald Kittler
    • , Wendy M. Blumenschein
    • , Terrill K. McClanahan
    • , Thomas Marbury
    • , Claus Zachariae
    • , Danlin Xu
    • , Xiaoli Shirley Hou
    • , Anish Mehta
    • , Anthe S. Zandvliet
    • , Diana Montgomery
    • , Frank van Aarle
    •  &  Sauzanne Khalilieh
  • Nature Communications | Article

    Skin-resident IL-17-producing γδT cells have an important role in skin inflammation but their development and trafficking is not well established. Here, Cai et al. unveil differences in the developmental requirements and functional regulation of two subsets of dermal γδT cells.

    • Yihua Cai
    • , Feng Xue
    • , Chris Fleming
    • , Jie Yang
    • , Chuanlin Ding
    • , Yunfeng Ma
    • , Min Liu
    • , Huang-ge Zhang
    • , Jie Zheng
    • , Na Xiong
    •  &  Jun Yan
  • Nature | Letter

    In mice, it is possible to induce a psoriasis-like condition by applying imiquimod; here, the production of interleukin-23 that is stimulated by such skin inflammation is shown to depend on the interaction of nociceptors expressing the Nav1.8 and TRPV1 channels with skin-resident dendritic cells.

    • Lorena Riol-Blanco
    • , Jose Ordovas-Montanes
    • , Mario Perro
    • , Elena Naval
    • , Aude Thiriot
    • , David Alvarez
    • , Silke Paust
    • , John N. Wood
    •  &  Ulrich H. von Andrian
  • Nature Medicine | Article

    Regulatory T (Treg) cells exhibit substantial phenotypic and functional plasticity. Hiroshi Takayanagi and his colleagues report that in autoimmune arthritis, a subset of Treg cells can lose Foxp3 expression and convert into TH17 cells. This conversion is mediated by synovial fibroblast-derived IL-6, and in vivo, these cells are osteoclastogenic and exacerbate arthritis. These findings suggest that a proportion of pathogenic TH17 cells in autoimmune disease may be derived from Treg cells.

    • Noriko Komatsu
    • , Kazuo Okamoto
    • , Shinichiro Sawa
    • , Tomoki Nakashima
    • , Masatsugu Oh-hora
    • , Tatsuhiko Kodama
    • , Sakae Tanaka
    • , Jeffrey A Bluestone
    •  &  Hiroshi Takayanagi
  • Nature | Article

    A global view of the genetic networks regulating the differentiation of TH17 cells is presented, based on temporal expression profiling, computational network reconstruction and validation of predicted interactions by nanowire-mediated siRNA perturbation.

    • Nir Yosef
    • , Alex K. Shalek
    • , Jellert T. Gaublomme
    • , Hulin Jin
    • , Youjin Lee
    • , Amit Awasthi
    • , Chuan Wu
    • , Katarzyna Karwacz
    • , Sheng Xiao
    • , Marsela Jorgolli
    • , David Gennert
    • , Rahul Satija
    • , Arvind Shakya
    • , Diana Y. Lu
    • , John J. Trombetta
    • , Meenu R. Pillai
    • , Peter J. Ratcliffe
    • , Mathew L. Coleman
    • , Mark Bix
    • , Dean Tantin
    • , Hongkun Park
    • , Vijay K. Kuchroo
    •  &  Aviv Regev
  • Nature Immunology | Article

    Exposure to interleukin 23 (IL-23) is required for the induction of pathogenic TH17 cells. Kuchroo and colleagues show that IL-23-dependent induction of the cytokine TGF-β3 produces a molecular signature characteristic of highly pathogenic TH17 cells.

    • Youjin Lee
    • , Amit Awasthi
    • , Nir Yosef
    • , Francisco J Quintana
    • , Sheng Xiao
    • , Anneli Peters
    • , Chuan Wu
    • , Markus Kleinewietfeld
    • , Sharon Kunder
    • , David A Hafler
    • , Raymond A Sobel
    • , Aviv Regev
    •  &  Vijay K Kuchroo