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.
Highlights
The interleukin 23 (IL-23) has emerged as a key pro-inflammatory cytokine involved in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis in murine models [1] and, more importantly, in humans
Specific deletion of Raptor and Rictor using the CD2-Cre system showed that mechanistic target of rapamycin complex 1 (mTORC1) activity was required for IL-1β and IL-23/IL-1β-induced dermal Tγδ cells proliferation, but interestingly, IL-17 production was not affected by Raptor deletion
We have collected information about specific molecular events that participate in IL-23 signaling cascade and how this knowledge can be taken further into the development of therapeutic intervention using small molecule inhibitors
Summary
The interleukin 23 (IL-23) has emerged as a key pro-inflammatory cytokine involved in the development of chronic inflammatory diseases, such as psoriasis, inflammatory bowel diseases, multiple sclerosis, or rheumatoid arthritis in murine models [1] and, more importantly, in humans. In addition to its pro-inflammatory function, IL-17 has a key role in the maintenance of barrier properties of epithelial tissues [19], and clinical trials targeting IL-17A and IL-17RA in patients with Crohn’s disease had to be terminated due to exacerbation of colitis [20,21] This outcome is consistent with the elevated Th17 cell response in the intestinal mucosa in the steady state, which is possibly directed against commensal bacterial antigens. Other approaches using hydrogen–deuterium exchange mass spectrometry (HDX-MS) identified macrocyclic small molecule against IL-23R that interfered with binding of IL-23 to the IL-23R [70] The efficacy of this small molecule still needs to be tested in in vivo models of IL-23-mediated pathologies, but overall, the strategies aimed to interfere with IL-23/IL-23R binding using small molecules and antagonistic peptides open new gateways for specific treatment of inflammatory diseases
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