The IL-23/IL-17 Pathway in Inflammatory Skin Diseases: From Bench to Bedside

Abstract

Interleukin-17 (IL-17) is an essential proinflammatory cytokine, which is mainly secreted by the CD4⁺ helper T cells (Th17 cells) and subsets of innate lymphoid cells. IL-17A is associated with the pathogenesis of inflammatory diseases, including psoriasis, atopic dermatitis, hidradenitis suppurativa, alopecia areata, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Interleukin-23 (IL-23) plays a pivotal role in stimulating the production of IL-17 by activating the Th17 cells. The IL-23/IL-17 axis is an important pathway for targeted therapy for inflammatory diseases. Emerging evidence from clinical trials has shown that monoclonal antibodies against IL-23, IL-17, and tumor necrosis factor are effective in the treatment of patients with psoriasis, atopic dermatitis, hidradenitis suppurativa, pityriasis rubra pilaris, pemphigus, and systemic sclerosis. Here, we summarize the latest knowledge about the biology, signaling, and pathophysiological functions of the IL-23/IL-17 axis in inflammatory skin diseases. The currently available biologics targeting the axis is also discussed.

Keywords: IL-17 family; IL-23; IL-23/IL-17 axis; psoriasis; targeted therapy.

Figure 1

IL-23/IL-17 signaling transduction. IL-23 is important in differentiation of Th17 cells, by promoting the production of IL-17A, IL-17F, TNF, and IL-6. IL-23 is heterodimeric and composed of IL-12p40 and IL-23p19. Binding to its receptors, IL-23 involves in phosphorylation of JAKs and TYK, as well as phosphorylation and dimerization of STAT3. Subsequently, STAT3 homodimers regulates the expression of ROR-γt to promote the gene expression. The combination of IL-17A/A, IL-17A/F, or IL-17F/F cytokine with IL-17RA and IL-17RC is found to be a crucial complex of immune response. IL-17R acts on Act1 through interaction platform of the SEFIR domain. Upon ligand binding, Act1 activates NF-κB, C/EBP family, and MAPK pathway by inducing various TRAF proteins. Act1 is essential for mediating ubiquitination of TRAF6, then TRAF6 triggers a positive reaction in multiple different pathways. TRAF6 recruits and stimulates the TAK1 and IKK complex, leading to activation of NF-κB pathway. IL-17R-Act1 complex together with TRAF4, MEKK3, and MEK5 to promote activation of ERK5. In addition, ACT1-TRAF2-TRAF5 complex is capable to maintain the mRNA stability targeting the IL-17 gene. The inhibitors A20 and TRAF3 are linked with IL-17RA, dependent on the CBAD. C/EBP, CCAAT/enhancer-binding proteins; NF-κB, canonical nuclear factor-κB; MAPK, mitogen-activated protein kinase; TRAF, tumor necrosis factor receptor associated factor; TAK1, transforming growth factor-β activated kinase 1; IKK, inhibitor of kappa B kinase; ERK5, extracellular signal-regulated kinase 5; RORγt, retinoid-related orphan receptor-γt; STAT3, signal transducer and activator of transcription 3; JAK2, Janus activated kinase 2; TYK2, tyrosine kinase 2.

Figure 2

T-cell immune axis and associated cytokines in the pathogenesis of psoriasis, hidradenitis suppurativa, atopic dermatitis, and alopecia areata. (A) Psoriasis develops through the aberrant activation of the dendritic cells producing IL-12 and IL-23. The dendritic cells induce the differentiation of the Th 17 cells and Th1 cells. IL-23 promotes the Th17 cells to secrete IL-17, IL-22, and TNF-α. In keratinocytes, IL-17 also stimulates production of antimicrobial peptides (S100A7/A8/A9 proteins and beta defensins). These cytokines promote keratinocyte proliferation and neutrophil recruitment, resulting in the formation of psoriatic plaques. (B) In hidradenitis suppurativa, the T cells involved in the pathogenesis of hidradenitis suppurativa include the Th1 and Th17 cells. IL-23 induces the differentiation of the Th17 cells and overexpression of IL-17. IL-17 induces the expression of the proinflammatory proteins (S100A8/A9) and NLRP3 in the keratinocytes. More inflammatory cytokines are recruited to the follicular unit and perilesional skin. (C) In atopic dermatitis, with impairment of the skin barrier in patients with atopic dermatitis, the damaged keratinocytes produce inflammatory cytokines (IL-17E). The cytokines stimulate the ILC2s to secrete type 2 cytokines (IL-5 and IL-13). IL-17E also inhibits the synthesis of FLG. IL-4, IL-13, and IL-31 directly stimulate the sensory nerves to promote pruritus. (D) In alopecia areata, the elevated IFN-γ levels in the perifollicular area activate the differentiation of the CD4⁺ T cells into various types of T cells, as shown. Th17 cells act on the hair follicle by producing proinflammatory mediators (IL-17, IL-21, IL-22, and IL-26), ultimately leading to the disruption of hair growth. TNF, tumor necrosis factor; NLRP3, NACHT, LRR, and NACHT, LRR, and PYD domains-containing protein 3; FLG, filaggrin; ILC2s, type 2 innate lymphoid cells; DC, dendritic cell.