Review
IL-17 in Chronic Inflammation: From Discovery to Targeting

https://doi.org/10.1016/j.molmed.2016.01.001Get rights and content

Trends

Interleukin-17 (IL-17) is a proinflammatory cytokine that plays a key role in host defense against extracellular bacterial and fungal infections.

T helper 17 (Th17) cells play a key role in the production of IL-17.

Increased production and contribution of IL-17 have been associated with several inflammatory disorders, including psoriasis, psoriatic arthritis, rheumatoid arthritis, and ankylosing spondylitis.

The first antibody against IL-17 was approved by the FDA and EMA in 2015 for the treatment of psoriasis.

Other IL-17 inhibitors are under development for a growing number of clinical indications. These include bispecific molecules targeting IL-17A and IL-17F as well as tumor necrosis factor (TNF) and IL-17A.

Inhibitors of Th17 differentiation include those that target IL-23 and the transcription factor retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt).

Interleukin-17 (IL-17) is a cytokine which elicits protection against extracellular bacterial and fungal infections and which plays important roles in inflammation. However, when produced in excess, it contributes to chronic inflammation associated with many inflammatory and autoimmune disorders. This has made IL-17 an attractive therapeutic target. The present review describes the structure of the IL-17 family, the IL-17 receptor complex, and the cells producing IL-17. The contributions of IL-17 to disease as well as new IL-17-based treatment options are discussed. Finally, the results of IL-17 or IL-17 receptor inhibitors in clinical trials are detailed. With a fruitful outlook, drug registration has now been granted for psoriasis psoriatic arthritis and ankylosing spondylitis, and also bears great potential in a growing number of conditions.

Introduction

The proinflammatory cytokine IL-17 was described fairly recently and is becoming an important therapeutic target for a growing number of chronic inflammatory diseases [1]. IL-17 plays a key role in host defense against extracellular bacterial and fungal infections [2]. Excess contribution of IL-17 has been associated with several inflammatory disorders including psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), and ankylosing spondylitis (AS). A first antibody against IL-17 (anti-IL-17) was approved in 2015 for the treatment of psoriasis. Other IL-17 pathway inhibitors are currently being tested for an increasing number of clinical indications relevant to various conditions [3].

This review first describes the structure and signaling pathways of IL-17 and IL-17-producing cells. The key functions of IL-17 are analyzed in the context of disease to introduce the treatment strategies. Finally, we highlight the benefits and limitations of inhibitors targeting IL-17 and the IL-17 receptor (IL-17R).

This discussion is timely, as it represents a good example of ‘translational research’, highlighting recent advances. It shows how quickly information from the discovery of IL-17 and T helper 17 (Th17) cells has been translated into the development of a successful therapy.

Section snippets

IL-17 Family

Human cytotoxic T lymphocyte-associated antigen 8 (CTLA8) was identified in 1993 and named IL-17 in 1995 [4]. The first bioactivity of human IL-17 was described in 1996 by showing the production of IL-6 and IL-8 from RA synoviocytes in response to IL-17. This immediately linked IL-17 to inflammation through IL-6 and to neutrophil recruitment through IL-8 [5].

Sequence screening identified an IL-17 family comprising six members from IL-17A (the first described IL-17) to IL-17F (Figure 1). IL-17A

Th17 Cells

The production of IL-17 by a subset of T cells was discovered in 1999 using T cell clones from the joints of RA patients [15]. The results were then confirmed in mice and the term Th17 subset was introduced in 2005 in the mouse as a T helper subset distinct from Th1 and Th2 cells 16, 17, 18. IL-12 had been identified as the key cytokine for the production of interferon gamma (IFNγ), the signature cytokine of the Th1 pathway. The new cytokine IL-23 was found to be associated with the Th17

The Biology of IL-17A

IL-17 has pleiotropic effects on multiple cell types. It plays a key role in host defense against infections but also in the development and chronicity of inflammatory disorders.

The Role of IL-17 in Inflammatory Diseases

IL-17 thus has two opposite contributions. Its deficiency leads to reduced control of infections, but its overproduction can lead to several chronic inflammatory diseases.

Tools to Target the IL-17 Pathway

Studies using cell systems as well as samples from patients and animal models have provided a strong justification for targeting IL-17 in human diseases, with the goal of controlling the harmful (and/or painful) manifestations associated with chronic inflammation. Two major options are currently being developed to target the IL-17 pathway, one acting directly on IL-17A and IL-17F or IL-17RA and the other acting upstream on the differentiation of Th17 cells (Table 1 and Figure 2, Key Figure).

Clinical Results with Inhibitors of IL-17 or IL-17R

A summary of the clinical results with antibodies directly targeting the IL-17 pathway is shown in Table 1.

Concluding Remarks

Inhibition of IL-17A and IL-17RA has already provided a major improvement in the care of psoriasis, achieving a level of response not seen before. Drug registration has been obtained for PsA and AS. These are already impressive achievements for a molecule discovered in 1995 and identified as a clinical target in 1999.

Other options based on IL-17 biology are now being tested, including bispecific antibodies against IL-17A and IL-17F and against TNFα and IL-17A, which may be of interest in cases

References (105)

  • C.E.M. Griffiths

    Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two Phase 3 randomised trials

    Lancet

    (2015)
  • H. Sofen

    Guselkumab (an IL-23-specific mAb) demonstrates clinical and molecular response in patients with moderate-to-severe psoriasis

    J. Allergy Clin. Immunol.

    (2014)
  • I.B. McInnes

    Secukinumab, a human anti-interleukin-17A monoclonal antibody, in patients with psoriatic arthritis (FUTURE 2): a randomised, double-blind, placebo-controlled, phase 3 trial

    Lancet

    (2015)
  • D. Baeten

    Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial

    Lancet

    (2013)
  • S. Mardiguian

    Anti-IL-17A treatment reduces clinical score and VCAM-1 expression detected by in vivo magnetic resonance imaging in chronic relapsing EAE ABH mice

    Am. J. Pathol.

    (2013)
  • D.W. Luchtman

    IL-17 and related cytokines involved in the pathology and immunotherapy of multiple sclerosis: current and future developments

    Cytokine Growth Factor Rev.

    (2014)
  • P. Miossec

    Interleukin-17 and type 17 helper T cells

    N. Engl. J. Med.

    (2009)
  • S. Cypowyj

    Immunity to infection in IL-17-deficient mice and humans

    Eur. J. Immunol.

    (2012)
  • P. Miossec et al.

    Targeting IL-17 and Th17 cells in chronic inflammation

    Nat. Rev. Drug Discov.

    (2012)
  • E. Rouvier

    CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene

    J. Immunol.

    (1993)
  • F. Fossiez

    T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines

    J. Exp. Med.

    (1996)
  • R.M. Onishi et al.

    Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease

    Immunology

    (2010)
  • S.L. Gaffen

    Structure and signalling in the IL-17 receptor family

    Nat. Rev. Immunol.

    (2009)
  • M.A. Kleinschek

    IL-25 regulates Th17 function in autoimmune inflammation

    J. Exp. Med.

    (2007)
  • S. Liu

    Crystal structures of interleukin 17A and its complex with IL-17 receptor A

    Nat. Commun.

    (2013)
  • S.L. Gaffen

    The IL-23–IL-17 immune axis: from mechanisms to therapeutic testing

    Nat. Rev. Immunol.

    (2014)
  • S. Zrioual

    IL-17RA and IL-17RC receptors are essential for IL-17A-induced ELR+ CXC chemokine expression in synoviocytes and are overexpressed in rheumatoid blood

    J. Immunol.

    (2008)
  • T. Aarvak

    IL-17 is produced by some proinflammatory Th1/Th0 cells but not by Th2 cells

    J. Immunol.

    (1999)
  • Z. Yao

    Human IL-17: a novel cytokine derived from T cells

    J. Immunol.

    (1995)
  • C. Infante-Duarte

    Microbial lipopeptides induce the production of IL-17 in Th cells

    J. Immunol.

    (2000)
  • D.J. Cua

    Interleukin-23 rather than interleukin-12 is the critical cytokine for autoimmune inflammation of the brain

    Nature

    (2003)
  • T. Korn

    IL-17 and Th17 Cells

    Annu. Rev. Immunol.

    (2009)
  • E. Bettelli

    Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells

    Nature

    (2006)
  • D.J. Cua et al.

    Innate IL-17-producing cells: the sentinels of the immune system

    Nat. Rev. Immunol.

    (2010)
  • T.J. Kenna

    Enrichment of circulating interleukin-17-secreting interleukin-23 receptor-positive γ/δ T cells in patients with active ankylosing spondylitis

    Arthritis Rheum.

    (2012)
  • T. Noordenbos

    Interleukin-17-positive mast cells contribute to synovial inflammation in spondylarthritis

    Arthritis Rheum.

    (2012)
  • M. Chabaud

    Enhancing effect of IL-1, IL-17, and TNF-α on macrophage inflammatory protein-3α production in rheumatoid arthritis: regulation by soluble receptors and Th2 cytokines

    J. Immunol.

    (2001)
  • P. Ye

    Interleukin-17 and lung host defense against Klebsiella pneumoniae infection

    Am. J. Respir. Cell Mol. Biol.

    (2001)
  • J.S. Cho

    IL-17 is essential for host defense against cutaneous Staphylococcus aureus infection in mice

    J. Clin. Invest.

    (2010)
  • H.R. Conti

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

    J. Exp. Med.

    (2009)
  • S. Kagami

    IL-23 and IL-17A, but not IL-12 and IL-22, are required for optimal skin host defense against Candida albicans

    J. Immunol.

    (2010)
  • L. de Beaucoudrey

    Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells

    J. Exp. Med.

    (2008)
  • A. Puel

    Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin-17 immunity

    Science

    (2011)
  • S. Okada

    Immunodeficiencies. Impairment of immunity to Candida and Mycobacterium in humans with bi-allelic RORC mutations

    Science

    (2015)
  • M. Chabaud

    Human interleukin-17: a T cell-derived proinflammatory cytokine produced by the rheumatoid synovium

    Arthritis Rheum.

    (1999)
  • S. Shahrara

    IL-17-mediated monocyte migration occurs partially through CC chemokine ligand 2/monocyte chemoattractant protein-1 induction

    J. Immunol.

    (2010)
  • M. Chabaud

    Enhancing effect of IL-17 on IL-1-induced IL-6 and leukemia inhibitory factor production by rheumatoid arthritis synoviocytes and its regulation by Th2 cytokines

    J. Immunol.

    (1998)
  • M.L. Toh

    Role of interleukin 17 in arthritis chronicity through survival of synoviocytes via regulation of synoviolin expression

    PLoS ONE

    (2010)
  • M.I. Koenders

    Interleukin-17 receptor deficiency results in impaired synovial expression of interleukin-1 and matrix metalloproteinases 3, 9, and 13 and prevents cartilage destruction during chronic reactivated streptococcal cell wall-induced arthritis

    Arthritis Rheum.

    (2005)
  • M. Chabaud et al.

    The combination of tumor necrosis factor alpha blockade with interleukin-1 and interleukin-17 blockade is more effective for controlling synovial inflammation and bone resorption in an ex vivo model

    Arthritis Rheum.

    (2001)
  • Cited by (0)

    View full text