Targeting Interleukin-17 as a Novel Treatment Option for Fibrotic Diseases

Abstract

Fibrosis is the end result of persistent inflammatory responses induced by a variety of stimuli, including chronic infections, autoimmune reactions, and tissue injury. Fibrotic diseases affect all vital organs and are characterized by a high rate of morbidity and mortality in the developed world. Until recently, there were no approved antifibrotic therapies. In recent years, high levels of interleukin-17 (IL-17) have been associated with chronic inflammatory diseases with fibrotic complications that culminate in organ failure. In this review, we provide an update on the role of IL-17 in fibrotic diseases, with particular attention to the most recent lines of research in the therapeutic field represented by the epigenetic mechanisms that control IL-17 levels in fibrosis. A better knowledge of the IL-17 signaling pathway implications in fibrosis could design new strategies for therapeutic benefits.

Keywords: IL-17; autoimmune; biological drugs; epigenetics; fibrosis.

Figure 1

Role of IL-17 cytokines in fibrotic autoimmune diseases IL-17 is produced by epithelial cells, dendritic cells, macrophages, CD4 T helper 17 (Th17), and gamma/delta T cells (Tγδ17 cells). IL-17 signaling promotes the production of pro-inflammatory factors such as granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor (TNFα), and the release of pro-inflammatory cytokines such as IL-6, IL-8, and IL-23. These pathogenic factors exacerbate chronic inflammation and, often through the epithelial-mesenchymal transition (EMT) process, cause the fibrotic evolution of autoimmune diseases.

Figure 2

The main cellular sources and targets of IL-17A and IL-17E in the EMT-mediated fibrotic evolution of autoimmune diseases. IL-17A/E contributes to idiopathic pulmonary fibrosis, primary biliary cirrhosis, and salivary gland fibrosis through the activation of EMT, which leads to fibroblast proliferation and differentiation into myofibroblasts. EMT (epithelial-mesenchymal transition); T h17 cells (T helper 17 cells).

Figure 3

The main epigenetic changes associated with differentiation of T h17 cells and upregulation of IL-17 are DNA methylation, histone post-translational modifications, and ncRNA (lncRNA and miRNAs). Bet proteins (bromodomain and extra-terminal domain); BRDs (bromodomains); DNMTs (DNA methyltransferases); ncRNA (non-coding RNA); lncRNA (long non-coding RNA); miRNA (microRNA); Dicer (Endoribonuclease Dicer C-terminal complex); TET (ten-eleven translocation); 2OG (2Oxoglutarate Oxygenase); IOX-1 (Histone demethylase inhibitor); Risc (RNA-induced silencing complex); T h17 cells (T helper 17 cells); the symbol “?” indicates that the mechanism has not yet been clarified.