Role of the IL23/IL17 Pathway in Crohn's Disease

Abstract

Crohn's disease (CD) is a chronic relapsing disorder of the gastrointestinal tract and represents one of the main entities of inflammatory bowel disease (IBD). CD affects genetically susceptible patients that are influenced by environmental factors and the intestinal microbiome, which results in excessive activation of the mucosal immune system and aberrant cytokine responses. Various studies have implicated the pro-inflammatory cytokines IL17 and IL23 in the pathogenesis of CD. IL23 is a member of the IL12 family of cytokines and is able to enhance and affect the expansion of pathogenic T helper type 17 (Th17) cells through various mechanisms, including maintenance of Th17 signature genes, upregulation of effector genes or suppression of repressive factors. Moreover, IL17 and IL23 signaling is able to induce a cascade of pro-inflammatory molecules like TNF, IFNγ, IL22, lymphotoxin, IL1β and lipopolysaccharide (LPS). Here, IL17A and TNF are known to mediate signaling synergistically to drive expression of inflammatory genes. Recent advances in understanding the immunopathogenetic mechanisms underlying CD have led to the development of new biological therapies that selectively intervene and inhibit inflammatory processes caused by pro-inflammatory mediators like IL17 and IL23. Recently published data demonstrate that treatment with selective IL23 inhibitors lead to markedly high response rates in the cohort of CD patients that failed previous anti-TNF therapy. Macrophages are considered as a main source of IL23 in the intestine and are supposed to play a key role in the molecular crosstalk with T cell subsets and innate lymphoid cells in the gut. The following review focuses on mechanisms, pathways and specific therapies in Crohn's disease underlying the IL23/IL17 pathway.

Keywords: Crohn’s disease; IL17/IL23 axis; anti-TNF therapy; inflammation; intestinal immunity; non-responder; resistance to apoptosis.

Figure 1

IL23 signaling in Crohn’s disease. IL23 is a heterodimer consisting of the unique subunits p19 and p40, the latter is shared with IL12. IL23 signals through its heterodimeric receptor complex consisting of the two subunits IL12Rβ1 and IL23R whereas IL23R is the unique subunit and IL-12Rβ1 shares the IL12 receptor complex. The IL23R complex signals through JAK kinase and STAT transcription factors. IL23 binding to its receptor activates Jak2 and Tyk2 kinases which then phosphorylates the receptor to form a docking site leading to the subsequent phosphorylation of STAT3 for the p19 subunit and STAT4 for the p40 subunit. IL23R signaling activates several pathways leading to transcription of several effector cytokine genes in CD including IL17A, IL17F and IL22.

Figure 2

Model of IL23 mediated resistance to apoptosis of mucosal CD4+ T cells in anti-TNF refractory Crohn’s disease patients. In anti-TNF refractory patients, TNFR2 bearing gut CD4+ T cells express the IL23R. Heightened production of IL23 from CD14+ macrophages leads to binding to the IL23R on CD4+TNFR2+ T cells and induction of STAT3 activation. This activation leads to the expansion of CD4+IL23R+TNFR2+ T cells that are resistant to apoptosis induction by anti-TNF antibodies, resulting in the perpetuation of mucosal inflammation.

Figure 3

IL23 in the development and activation of Th17 cells. In chronic inflammation, antigen-presenting cells like dendritic cells and macrophages are the main producers of IL23, which promotes together with other cytokines like IL1, IL6 and TGFβ the development of IL17 producing pathogenic Th17 cells. The differentiation of Th17 cells is prompted by the synergistically working of STAT3 and RORγt leading to the upregulation of the IL23R on Th17 cells and the release of other pro-inflammatory cytokines like IL17A, IL17F, IL6 or TNFα. This in turn leads to the production of IL23 mainly by macrophages. IL23 is on the one hand important for the maintenance and expansion of the Th17 lineage and in addition acts mainly on macrophages in an autocrine manner.

Figure 4

Therapeutic approaches targeting IL23 and IL17 signaling. Ustekinumab and briakinumab specifically blocks the IL12/IL23 subunit p40 in CD patients whereas risankizumab, brazikumab, guselkumab and mirikizumab selectively block the unique subunit p19. Activated Th17 cells produce large amounts of IL17. Secukinumab directly binds to IL17A and thereby inhibits the interaction with the IL17 receptor (IL17R). Brodalumab directly binds to the IL17R causing an inhibition of IL17 ligand binding (A and F) to their receptor.