Local and systemic effects of IL-17 in joint inflammation: a historical perspective from discovery to targeting

Abstract

The role of IL-17 in many inflammatory and autoimmune diseases is now well established, with three currently registered anti-IL-17-targeted therapies. This story has taken place over a period of 20 years and led to the demonstration that a T cell product could regulate, and often amplify, the inflammatory response. The first results described the contribution of IL-17 to local features in arthritis. Then, understanding was extended to its systemic effects, with a focus on cardiovascular aspects. This review provides a historical perspective of these discoveries focused on arthritis, which started in 1995, followed 10 years later by the description of Th17 cells. Today, IL-17 inhibitors for three chronic inflammatory diseases have been registered. More options are now being tested in ongoing and future clinical trials. Inhibitors of IL-17 family members and Th17 cells ranging from antibodies to small molecules are under active development. The identification of patients with IL-17-driven disease is a key target for the improved selection of patients expected to have a strongly positive response.

Keywords: Arthritis, targeting; Inflammation; Interleukin-17; Th17 cells.

Fig. 1

Local effects of IL-17 in combination with other proinflammatory cytokines. The key monocyte-derived cytokines TNF and IL-1 act on stromal cells to induce the production of IL-6 and chemokines. This effect is amplified by IL-17, often through synergistic interactions. The resulting effects act on vessels, inducing pathogenic cell migration. This induces the activation of local stromal cells and migrated pathogenic cells and increases their survival. Consequently, these effects result in changes to the matrix structure and metabolism. The net result depends on the tissue involved and its anatomic localization. In whole bone, where osteoclasts are in contact with osteoblasts, these cytokines induce bone destruction. In tendons and ligaments, which lack osteoclasts, the same cytokines induce stromal cell differentiation into osteoblasts, resulting in ectopic bone formation. This figure is focused on differences in the various presentations of arthritis. Most of the effects can be applied to other chronic and acute conditions

Fig. 2

Systemic effects of IL-17 in combination with other proinflammatory cytokines. Regarding local effects, the key monocyte-derived cytokines TNF and IL-1 act on stromal cells to induce the production of IL-6 and chemokines. This effect is amplified by IL-17, often through synergistic interactions. These effects act on the brain, bone marrow, vessels, liver, and muscles. This figure depicts the overall clinical picture for many chronic and acute conditions, including the cytokine storm in COVID-19

Fig. 3

Options for directly and indirectly targeting IL-17. Direct options to target IL-17 include targeting the IL-17A homodimer and IF-17A/F heterodimer with an anti-IL-17A monoclonal Ab and targeting the IL-17RA chain of the IL-17 receptor with a monoclonal anti-IL-17RA Ab. Another option is targeting both IL-17A and IL-17F with a bispecific Ab. Indirect options to target IL-17 include the use of inhibitors of Th17 cell differentiation with anti-IL-1, anti-IL-6, and anti-IL-23 Abs. Another option is the use of small molecules to target Rorγt/Rorc