Trends in Molecular Medicine
ReviewIL-17 in Chronic Inflammation: From Discovery to Targeting
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
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