Decoding IL-23 Signaling Cascade for New Therapeutic Opportunities

Abstract

The interleukin 23 (IL-23) is a key pro-inflammatory cytokine in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis. The pathological consequences of excessive IL-23 signaling have been linked to its ability to promote the production of inflammatory mediators, such as IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα) by target populations, mainly Th17 and IL-17-secreting TCRγδ cells (Tγδ17). Due to their pivotal role in inflammatory diseases, IL-23 and its downstream effector molecules have emerged as attractive therapeutic targets, leading to the development of neutralizing antibodies against IL-23 and IL-17 that have shown efficacy in different inflammatory diseases. Despite the success of monoclonal antibodies, there are patients that show no response or partial response to these treatments. Thus, effective therapies for inflammatory diseases may require the combination of multiple immune-modulatory drugs to prevent disease progression and to improve quality of life. Alternative strategies aimed at inhibiting intracellular signaling cascades using small molecule inhibitors or interfering peptides have not been fully exploited in the context of IL-23-mediated diseases. In this review, we discuss the current knowledge about proximal signaling events triggered by IL-23 upon binding to its membrane receptor to bring to the spotlight new opportunities for therapeutic intervention in IL-23-mediated pathologies.

Keywords: IL-23; autoimmunity; inflammatory disease; interleukin 17; interleukin 23; multiple sclerosis; psoriasis; signaling.

Figure 1

Role of interleukin 23 (IL-23) in chronic inflammatory diseases. IL-23 is produced by dendritic cells (DCs) and activated macrophages, and its actions are mainly mediated by the CD4 T helper subset Th17, a distinct subpopulation of gamma/delta T cells (Tγδ17 cells), subsets of natural killer T (NKT) cells, and type 3 innate lymphoid cells (ILC3s). IL-23 signaling promotes the production of pro-inflammatory mediators (IL-17, IL-22, granulocyte-macrophage colony-stimulating (GM-CSF), or the tumor necrosis factor (TNFα)) by target populations. These pathogenic mediators promote the recruitment and activation of granulocytes and macrophages, causing the tissue damage that induce chronic inflammation and, finally, the development of clinical symptoms.

Figure 2

IL-23 proximal signaling cascade: Janus tyrosine kinases (JAKs)/signal transducer and activator of transcription (STATs) module. IL-23 receptor complex is associated with the JAK family members Jak2 and Tyk2. IL-23 binding to the IL-23R promotes JAKs activation and phosphorylation of Tyr residues (pY) in both the JAKs themselves and in the IL-23R cytoplasmic tail, creating docking sites for STAT3 monomers through Src homology 2 domains (SH2). Active Jak2/Tyk2 phosphorylate STAT3 monomers, leading to dimerization, nuclear translocation, and DNA binding to target gene promoters.

Figure 3

New players in IL-23 proximal signaling events. IL-23 promotes phosphorylation of the myosin regulatory light chain (RLC) via Jak2 and ROCK activation, and IL-23 induces migration of Tγδ17 and Th17 cells in a ROCK dependent manner. The association of the Dedicator of cytokinesis 8 (DOCK8) to STAT3 is required for sustained STAT3 phosphorylation and IL-22 production downstream IL-23. IL-23 triggered the phosphorylation of pyruvate kinase isoform PKM2-Ser37 residue, promoted its nuclear translocation, and induced the expression of PKM2 downstream target genes. IL-23 induces CD69 expression, and CD69 associates with LAT1/CD98 amino acid transporter to promote L-Trp uptake. Derivatives from L-Trp metabolism activate AhR to induce IL-22 production in Tγδ17 cells.

Figure 4

IL-23-regulated transcription factors. IL-23 induces the expression of the transcription factor retinoic acid receptor-related orphan receptor-γt (RORγt), master regulator of Th17 cell differentiation and essential for IL-17 production and IL-23R expression. IL-23 promotes the expression of the transcription factor Blimp1, required for GM-CSF production and IL-23R expression in Th17 cells. IL-23 stimulation increases the expression of the chromatin organizer Satb1 that in turn promotes Bhlhe40 expression that are required for GM-CSF production. IL-23 promotes IκBα phosphorylation and proteasomal degradation, allowing NF-κB translocation to the nucleus and the induction of the receptor activator of NF-κB ligand (RANKL) expression, a key osteoclastogenic cytokine involved in bone destruction and arthritis pathology.

Figure 5

IL-23 and IL-1β: signaling crosstalk. The combined action of IL-23 and IL-1β greatly increases the production of IL-17, IL-22, and GM-CSF. Right, IL-23 and IL-1β signaling cascades at a glance: IL-23 signaling cascade is mediated by the JAK/STAT module, while IL-1β signal is transduced by MyD88/IRAKs/TRAF6 module. MyD88/IRAKs/TRAF6 induce the activation of several phosphoproteins and transcription factors. Left, IL-1β stimulation decreases IL-23-induced expression of Socs3 in an NF-κB-dependent manner, and decreased Socs3 expression upon IL-23/IL-1β stimulation leads to an increased STAT3 phosphorylation. IL-1β-induced NF-κB/RelA activation increased the binding of IL-23-induced STAT3 to regulatory elements in the Il17a/f locus. IL-23 and IL-1β promote mTORC1 and mTORC2 activation. IL-23/IL-1β activation of mTORC2 induces the expression of the transcription factor IRF4, required for IL-17 production and Tγδ cell proliferation. IL-23/IL-1β-induced mTORC1 activation promotes Tγδ cell proliferation and induces RORγt and AhR expression in neutrophils. IL-23/IL-1β co-stimulation increases the expression of LAT1 and induces the activation of mTORC1 and the proliferation in Tγδ17 cells.