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Targeting IL-17 and TH17 cells in chronic inflammation

Key Points

  • Interleukin-17 (IL-17) is a pro-inflammatory cytokine that contributes to the pathogenesis of several inflammatory diseases.

  • The key IL-17 family members are IL-17A and IL-17F, which share a 50% sequence homology. They bind to an IL-17 receptor (IL-17R) complex that is composed of two chains, known as IL-17RA and IL-17RC. IL-17A and IL-17F interact with inflammatory cytokines such as IL-1 and tumour necrosis factor, often in a synergistic manner.

  • IL-17A and IL-17F are the key cytokines produced by T helper 17 (TH17) cells. These cells are crucial for the control of infections, especially extracellular bacterial and fungal infections. They also contribute to epithelial and mucosal protection.

  • Overexpression of IL-17 and TH17 cells contributes to tissue inflammation that is accompanied by matrix destruction, autoimmunity and vascular activation.

  • Positive results have been obtained in clinical trials with two monoclonal antibodies against IL-17A in psoriasis, rheumatoid arthritis and ankylosing spondylitis. Positive results in a clinical trial in psoriasis have been obtained with a monoclonal antibody targeting IL-17RA.

  • Dual inhibitors of IL-17A and IL-17F, of IL-17A and tumour necrosis factor as well as inhibitors of IL-17R signalling are at the preclinical stage of development.

Abstract

The key role of interleukin-17 (IL-17) and T helper 17 (TH17) cells in tissue inflammation, autoimmunity and host defence led to the experimental targeting of these molecules in mouse models of diseases as well as in clinical settings. Moreover, the demonstration that IL-17 and TH17 cells contribute to local and systemic aspects of disease pathogenesis, as well as the finding that the IL-17–TH17 cell pathway is regulated by IL-23, prompted the identification of inhibitors. These inhibitors include biotechnology products that target IL-23 as well as the leading member of the IL-17 family, IL-17A, and one of its receptors, IL-17 receptor A. Several clinical trials of these inhibitors are underway, and positive results have been obtained in psoriasis, rheumatoid arthritis and ankylosing spondylitis. This Review focuses on the current knowledge of the IL-17–TH17 cell pathway to better understand the positive as well as potential negative consequences of targeting them.

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Figure 1: Structure of IL-17 and its interaction with IL-17R.
Figure 2: Key functions of IL-17 and its role in inflammation and matrix destruction.
Figure 3: Key functions of the IL-17–TH17 pathway and its role in host defence.
Figure 4: Tools for targeting the IL-17–TH17 pathway.

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Acknowledgements

P.M.'s work is supported by grants from the Institut Mérieux, the Hospices Civils de Lyon (HCL) and the Institut Universitaire de France (IUF). J.K.K.'s work was supported by the National Heart, Lung, and Blood Institute (NHBLI) grant R37-HL079142.

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Glossary

T helper 17 cells

(TH17 cells). A lineage of CD4+ T cells that are defined by the expression of interleukin-17A (IL-17A) and IL-17F; the development of these cells is controlled by the transcription factors retinoid-related orphan receptor-α (RORA) and RORC.

Cystine knots

Motifs that were first described in nerve growth factor, wherein two disulphide bridges are formed from paired cysteine molecules. This motif conveys protein stability.

CCAAT/enhancer-binding proteins

(C/EBPs). A family of transcription factors that regulate gene expression by interacting with the CCAAT box motif.

CC′ loop region

A region of the cytoplasmic SEFIR domain (named after SEF and a homologous TIR (Toll/IL-1R) domain) of interleukin-17 (IL-17) receptor, defined by the third strand (C) and the third helix (C′).

Memory CD4+ T cells

A putative subpopulation of relatively long-lived CD4+ T cells that have interacted with their cognate antigen.

TH1-associated diseases

Diseases attributed to interferon-γ (IFNγ)-producing CD4+ T cells.

STAT4

Signal transducer and activator of transcription 4; a member of the STAT protein family that is required for the development of T helper 1 (TH1) CD4+ T cells.

STAT6

Signal transducer and activator of transcription 6; a member of the STAT protein family that is required for the development of T helper 2 (TH2) CD4+ T cells.

Naive T cells

T cells that have not interacted with their cognate antigen.

RORC

Retinoid-related orphan receptor-γ. RORC encodes a transcription factor that is expressed in interleukin-17 (IL-17)-producing cells.

γδ T cells

A subset of T cells that express a T cell receptor consisting of a γ- and δ-chain as opposed to an α- and β-chain. These cells are enriched at mucosal surfaces: for example, in the gastrointestinal tract, skin and lung.

Invariant NK cells

(iNK cells). A subset of natural killer (NK) cells that express an invariant T cell receptor.

Fcɛ receptor I

A protein that serves as the high-affinity receptor for immunoglobulin E.

TH2-type responses

Immune responses associated with the T helper 2 (TH2) subset of CD4+ T cells, such as allergy or immune responses to helminth infection.

Acute phase response

An increase in levels of plasma proteins in response to acute inflammation.

Matrix metalloproteinases

A family of zinc-dependent proteases that can degrade extracellular matrix proteins.

Receptor activator of NF-κB ligand

(RANKL). A member of the tumour necrosis factor superfamily expressed on osteoblasts that can activate osteoclasts to mediate bone resorption.

B cells

A subpopulation of lymphocytes that develop in the bone marrow and mediate humoral (that is, antibody-mediated) immunity.

TNF receptor 2

Tumour necrosis factor (TNF) receptor 2 (TNFR2; also known as p75 or TNFRSF1B); a 75 kDa receptor that can bind to TNF and lymphotoxin-α.

Neutrophilia

An increased density of neutrophils in peripheral blood.

Mucosal immunity

Immune responses that occur at mucosal membranes.

Apoe−/− mice

Mice with a homozygous deletion in the apolipoprotein E (Apoe) gene; these mice are a model of hypercholesterolaemia.

ACR20 response rate

The response rate of patients in clinical trials for rheumatoid arthritis who show a 20% decrease in the clinical American College of Rheumatology (ACR) score.

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Miossec, P., Kolls, J. Targeting IL-17 and TH17 cells in chronic inflammation. Nat Rev Drug Discov 11, 763–776 (2012). https://doi.org/10.1038/nrd3794

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