IL-23 past, present, and future: a roadmap to advancing IL-23 science and therapy

Abstract

Interleukin (IL)-23, an IL-12 cytokine family member, is a hierarchically dominant regulatory cytokine in a cluster of immune-mediated inflammatory diseases (IMIDs), including psoriasis, psoriatic arthritis, and inflammatory bowel disease. We review IL-23 biology, IL-23 signaling in IMIDs, and the effect of IL-23 inhibition in treating these diseases. We propose studies to advance IL-23 biology and unravel differences in response to anti-IL-23 therapy. Experimental evidence generated from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve upon current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate optimal identification of patients and, thereby, outcomes.

Keywords: IL-23; cytokine; immune-mediated inflammatory diseases; inflammatory bowel disease; psoriasis; psoriatic arthritis.

Figure 1

Schematic representation of IL-23–producing cells and IL-23 target cells implicated in PsO, PsA, and IBD pathogenesis. Myeloid cells are considered major producers of IL-23 in response to endogenous (eg, IL-6, TGF-β) or exogenous (eg, inflammation, infection) stimuli. Studies assessing the precise phenotypic and transcriptomic signature of IL-23–producing myeloid subsets in different IMIDs are ongoing. However, monocytes/macrophages, mononuclear phagocytes, and inflammatory monocyte–like cells that express FcγRI/CD64 have been identified as IL-23–producing cells in patients with psoriatic disease and IBD (9, 10). Semimature dendritic cells and neutrophils, which may also express FcγRI/CD64, have been identified as producers of IL-23 in PsO and IBD, respectively, as well (11, 12). High local concentrations of IL-23 produced by these cells can promote proliferation and survival of Th17 cells and stimulate other immune cells that express the IL-23 receptor and RORγt, including γδ T cells, NKTs, “natural” Th17 cells, Tc17 cells, and ILC3s, which collectively are termed type-17 cells (2). Th17 and type-17 cells induce local tissue inflammation via release of IL-17A, IL-17F, IL-22, and GM-CSF. Notably, induction of IL-17A and IL-17F production from Th17 cells does not require IL-23R signaling, but activation of the IL-23 receptor is required for pathogenic effector Th17 cell responses. FcγRI, Fc-γ receptor I; GM-CSF, granulocyte macrophage colony-stimulating factor; IBD, inflammatory bowel disease; IL, interleukin; IL-23R, IL-23 receptor; ILC, innate lymphoid cell; IMID, immune-mediated inflammatory disease; MAIT, mucosal-associated invariant T cell; NKT, natural killer T cell; PsA, psoriatic arthritis; PsO, psoriasis; RORγt, retinoic acid receptor–related orphan receptor-γt; Tc17, IL-17⁺ CD8⁺ T; Th, T helper.

Figure 2

Timeline of critical discoveries related to the IL-23 pathway. Prior to the discovery of IL-23, the accepted paradigm proposed to divide CD4⁺ Th cells into 2 subsets (IFN-γ–producing Th1 cells and IL-4–producing Th2 cells) to explain the tendency of T cells to diverge into those that drive either a cellular or humoral immune response (29). However, this binary hypothesis did not explain the full spectrum of immune responses. IFN-γ–producing Th1 cells and IL-4–producing Th2 cells are dependent on STAT1 and STAT6, respectively, which did not adequately explain the regulation of STAT3-dependent CD4⁺ T cells in autoimmunity and infection. In addition, neutrophil recruitment and activation are major hallmarks of inflammation, and Th1 and Th2 cells do not promote significant neutrophil-mediated tissue injury. Following its discovery (30), IL-23 was shown to be essential for development of experimental autoimmune encephalomyelitis and was implicated in the growth, expansion, and survival of a subset of pathogenic T lymphocytes characterized by the production of IL-17A, IL-17F, IL-6, and TNF that is distinct from Th1 and Th2 cells, now known as Th17 cells (31, 32). TGF-β and IL-6 were later shown to be required to facilitate differentiation of naive T cells into Th17 cells (–35), and the IL-23 signaling pathway was then linked to IMIDs by GWAS that identified variants of the IL23R gene that are associated with IBD and psoriatic disease susceptibility (36, 37). A little more than a decade later, the first phase 3 clinical trial results showing efficacy of an IL-23p19 subunit inhibitor (guselkumab) in an IMID (PsO) were published, followed over the next several years by results in PsA, CD, and UC (–7, 38). CD, Crohn’s disease; GM-CSF, granulocyte macrophage colony-stimulating factor; GWAS, genome-wide association study; IBD, inflammatory bowel disease; IFN-γ, interferon-γ; IL, interleukin; IL23R, IL-23 receptor gene; IMID, immune-mediated inflammatory disease; PsA, psoriatic arthritis; PsO, psoriasis; STAT, signal transducer and activator of transcription; TGF-β, transforming growth factor-β; Th, T helper; UC, ulcerative colitis.

Figure 3

Schematic representation of IL-23 and IL-12 and their receptors, with summary of associated effector cells, cytokines, and immune function. IL-23 comprises the p19 and p40 subunits that bind to the IL-23R and IL-12Rβ1 subunits of the IL-23 receptor, respectively. IL-12 also contains the p40 subunit, which pairs with the p35 subunit that binds to IL-12Rβ2 (39). Engagement of the IL-23 receptor results in formation of a cytokine-receptor ternary complex that includes IL-23, IL-23R, and IL-12Rβ1 (40). Formation of this ternary complex activates a range of JAKs, including JAK2 and TYK2, which associate with intracellular domains of the receptor subunits and initiate specific signaling cascades (–42). IL-23 activates pathogenic functions of CD4⁺ Th17 cells and stimulates other effector cells, including γδ T cells, NKTs, “natural” Th17 cells, Tc17 cells, MAITs, and ILC3s, that collectively produce IL-17A, IL-17F, IL-22, GM-CSF, IL-6, and TNF-α (32, 41). In contrast, IL-12 promotes differentiation of Th1 cells and activates NK cells, ILC1s, and cytotoxic T cells leading to production of IFN-γ, TNF-α, granzymes, and perforin (41). In addition, IL-23 activation of transcription factors, including STAT3, RORγt, and Blimp-1, enhances IL23R expression and, in a positive-feedback loop, can amplify IL-23 signaling (39, 43). RORγt represents a particularly notable IL-23–induced transcription factor essential for differentiation of naive T cells into Th17 cells. Simultaneous priming with TGF-β, IL-6, and IL-1 activates RORγt and induces expression of the IL-23 receptor, thus amplifying IL-23 signaling, which is critical for maturation and stabilization of the proinflammatory Th17 phenotype (18, 34, 35). The IL-23/Th17 pathway is important for protection against extracellular bacterial and fungal infections, while it appears to be dispensable for protection against most intracellular infections. In contrast, the IL-12/Th1 pathway is required for host responses to intracellular pathogens (44). Blimp-1, B lymphocyte–induced maturation protein 1; GM-CSF, granulocyte macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; IL-12Rβ1, IL-12 receptor, β1 subunit; IL-12Rβ2, IL-12 receptor, β2 subunit; IL-23R, IL-23 receptor subunit; ILC, innate lymphoid cell; JAK, Janus kinase; MAIT, mucosal-activated invariant T cell; NKT, natural killer T cell; P, phosphoryl group; RORγt, retinoic acid receptor–related orphan receptor-γt; STAT, signal transducer and activator of transcription; Tc17, IL-17⁺ CD8⁺ T; Th, T helper; TNF-α, tumor necrosis factor-α; TYK, tyrosine kinase.