Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective

Abstract

Chronic inflammatory diseases like psoriasis, Crohn's disease (CD), multiple sclerosis (MS), rheumatoid arthritis (RA), and others are increasingly recognized as disease entities, where dysregulated cytokines contribute substantially to tissue-specific inflammation. A dysregulation in the IL-23/IL-17 axis can lead to inflammation of barrier tissues, whereas its role in internal organ inflammation remains less clear. Here we discuss the most recent developments in targeting IL-17 for the treatment of chronic inflammation in preclinical models and in patients afflicted with chronic inflammatory diseases.

Figure 1.

IL-17 cytokine and receptor family. Schematic overview of the known heterodimeric IL-17 receptor complexes with their respective IL-17 cytokines. Unknown coreceptors and ligands are displayed with dashed lines. IL-17 receptors share a common structure with two extracellular fibronectin II–like (FN) domains and an intracellular SEFIR domain. Downstream signaling events depend on the adaptor Act1. In the canonical pathway Act1 ubiquitinates TRAF6, leading to recruitment of TAK1 and triggering of NF-κB, MAPK pathways, and the CCAAT-enhancer-binding proteins (C/EBP) pathway. The noncanonical pathway is initiated by phosphorylation of Act1 by inducible IκB kinase (IKKi) and the subsequent formation of a complex with TRAF2, TRAF5, and mRNA stabilizing factor human antigen R (HuR), which increases the half-life of several mRNAs. Ub, ubiquitin; P, phosphoryl group.

Figure 2.

Cellular sources and targets of IL-17A/F. Overview of described cellular sources (top row) and targets (bottom row) of IL-17A/F. IL-23 induces IL-17 production in CD4 T cells (Aggarwal et al., 2003), γδ T cells (Sutton et al., 2009), NK(T) cells (Michel et al., 2007; Passos et al., 2010), ILCs (Buonocore et al., 2010), and CD8 T cells (Happel et al., 2003). The dependence of IL-23 on other IL-17–producing cells as Paneth cells (Takahashi et al., 2008), mast cells (Lin et al., 2011; Mashiko et al., 2015), and B cells (Schlegel et al., 2013) has to be determined. Whether myeloid cells (depicted in gray) produce IL-17 is still controversially discussed (Ferretti et al., 2003; Song et al., 2008; Li et al., 2010; Tamassia et al., 2018). IL-17RA is ubiquitously expressed, but the main targets of IL-17 include endothelial cells, epithelial cells, fibroblasts (Fossiez et al., 1996), osteoblasts (Kotake et al., 1999), and chondrocytes (Shalom-Barak et al., 1998). Less-studied potential cellular targets of IL-17 (depicted in gray) are myeloid cells and B and T cells.

Figure 3.

Effects of targeting IL-17 and IL-23 in psoriasis and Crohn’s disease. The neutralization of IL-23 cures skin inflammation in psoriasis by interfering with the IL-23/IL-17 axis. Abrogation of pathogenic IL-23–dependent IL-17 production prevents IL-17–driven keratinocyte proliferation and neutrophil recruitment. IL-23–independent IL-17 production is preserved, which is needed for protection from Candida infections. Direct inhibition of IL-17 also reduces skin inflammation, but compromises host defense against Candida, leading to increased rates of candidiasis. Intestinal inflammation characteristic of Crohn’s disease is improved upon IL-23 neutralization, which inhibits mainly IL-23–dependent IL-17 production and thus interferes with disease-driving mechanisms like neutrophil attraction. IL-23 neutralization spares IL-23–independent IL-17 production important for maintenance of epithelial barrier function and control of the commensal bacteria in the gut. In contrast, direct IL-17 inhibition exacerbates intestinal skin inflammation due to abrogation of the protective functions of IL-17 on epithelial integrity and microbiota control. This leads to invasion of luminal bacteria with a subsequent influx of immune cells and secretion of other pro-inflammatory cytokines to mount an immune response, which perpetuates intestinal inflammation.