The forgotten key players in rheumatoid arthritis: IL-8 and IL-17 - Unmet needs and therapeutic perspectives

Abstract

Despite the relevant advances in our understanding of the pathogenetic mechanisms regulating inflammation in rheumatoid arthritis (RA) and the development of effective therapeutics, to date, there is still a proportion of patients with RA who do not respond to treatment and end up progressing toward the development of joint damage, extra-articular complications, and disability. This is mainly due to the inter-individual heterogeneity of the molecular and cellular taxonomy of the synovial membrane, which represents the target tissue of RA inflammation. Tumor necrosis factor alpha (TNFα) and interleukin-6 (IL-6) are crucial key players in RA pathogenesis fueling the inflammatory cascade, as supported by experimental evidence derived from in vivo animal models and the effectiveness of biologic-Disease Modifying Anti-Rheumatic Drugs (b-DMARDs) in patients with RA. However, additional inflammatory soluble mediators such as IL-8 and IL-17 exert their pathogenetic actions promoting the detrimental activation of immune and stromal cells in RA synovial membrane, tendons, and extra-articular sites, as well as blood vessels and lungs, causing extra-articular complications, which might be excluded by the action of anti-TNFα and anti-IL6R targeted therapies. In this narrative review, we will discuss the role of IL-8 and IL-17 in promoting inflammation in multiple biological compartments (i.e., synovial membrane, blood vessels, and lung, respectively) in animal models of arthritis and patients with RA and how their selective targeting could improve the management of treatment resistance in patients.

Keywords: chronic pain; interleukin-17; interleukin-8; organ damage; rheumatoid arthritis.

Figure 1

Pathogenetic actions of interleukin-8 (IL-8) and IL-17 on immune and stromal cells in multiple biological compartments in rheumatoid arthritis. (Left section) Schematic representation of the pathogenetic actions of IL-8 in the synovial tissue, blood vessel wall, and alveolar space in RA. Synovial tissue: The release of IL-8 by resident macrophages and fibroblast-like synoviocytes (FLS) plays a chemotactic action promoting the recruitment of immune cells toward the synovial tissue fueling tissue inflammation and promoting osteoclasts differentiation and activation leading to bone damage. Vessel wall: The release of IL-8 by infiltrating macrophages promotes the proliferation of smooth muscle cells and the activation of endothelial cells promoting plaque progression. Alveolar space: The release of IL-8 by alveolar macrophages enhances myeloid cell migration from circulation and promotes the development of hyper-fibrotic macrophages. Moreover, the release of IL-8 from mesenchymal cells induces their migration and proliferation in an autocrine loop. (Right section) Schematic representation of the pathogenetic actions of IL-17 in the synovial tissue, blood vessel wall, and alveolar space in RA. Synovial tissue: The release of IL-17 by Th17 lymphocytes promotes the activation of synovial macrophages and FLS contributing to the chronicity of synovitis. Moreover, IL-17 is a potent inducer of osteoclast/chondrocyte activation contributing to bone and cartilage damage. Vessel wall: The release of IL-17 by adaptive and innate immune cells promotes the chemotaxis of immune cells within the vessel plaque and promotes endothelial cell apoptosis, accelerating the atherosclerotic process and leading to increased cardiovascular risk. Alveolar space: The release of IL-17 interferes with the pneumocyte I autophagy process and its release by pneumocytes type II enhances fibroblast proliferation, which contributes to extracellular matrix deposition and lung fibrosis.