Distinct Roles of IL-23 and IL-17 in the Development of Psoriasis-Like Lesions in a Mouse Model

Abstract

Psoriasis is an inflammatory disease with dynamic interactions between the immune system and the skin. The IL-23/Th17 axis plays an important role in the pathogenesis of psoriasis, although the exact contributions of IL-23 and IL-17 in vivo remain unclear. K5.Stat3C transgenic mice constitutively express activated Stat3 within keratinocytes, and these animals develop skin lesions with histological and cytokine profiles similar to those of human plaque psoriasis. In this study, we characterized the effects of anti-mouse IL-17A, anti-mouse IL-12/23p40, and anti-mouse IL-23p19 Abs on the development of psoriasis-like lesions in K5.Stat3C transgenic mice. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs greatly inhibited 12-O-tetradecanoylphorbol-13-acetate–induced epidermal hyperplasia in the ears of K5.Stat3C mice, whereas the inhibitory effect of an anti–IL-17A Ab was relatively less prominent. Treatment with anti–IL-12/23p40 or anti–IL-23p19 Abs markedly lowered transcript levels of Th17 cytokines (e.g., IL-17 and IL-22), β-defensins, and S100A family members in skin lesions. However, anti–IL-17A Ab treatment did not affect mRNA levels of Th17 cytokines. Crossing IL-17A–deficient mice with K5.Stat3C mice resulted in partial attenuation of 12-O-tetradecanoylphorbol-13-acetate–induced lesions, which were further attenuated by anti–IL-12/23p40 Ab treatment. FACS analysis of skin-draining lymph node cells from mice that were intradermally injected with IL-23 revealed an increase in both IL-22–producing T cells and NK-22 cells. Taken together, this system provides a useful mouse model for psoriasis and demonstrates distinct roles for IL-23 and IL-17.

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…106 In contrast to targeting IL-23 signaling, the inhibitory effects of targeting IL-17 signaling are less prominent in these animal models, indicating that alternative pathways may also contribute to the development of skin inflammation. 103,104,106 On a cellular level, IL-17 synergizes with other cytokines, such as TNFα, IFNγ or IL-22, to induce the production of proinflammatory cytokines, chemokines and antimicrobial peptides from keratinocytes. [107][108][109] Because the IL-23-Th17-IL-17 axis is critical for the pathogenesis of psoriasis, antibody targeting therapies that target IL-17 signaling (that is, brodalumab, ixekizumab and secukinumab) or IL-23 signaling (that is, ustekinumab, briakinumab, tildrakizumab and guselkumab) are being rapidly developed and have shown prominent outcomes in treating psoriatic diseases in different clinical trials.…”

“…[103][104][105] K5.Stat3C transgenic mice in which Stat3 is constitutively activated in keratinocytes develop skin lesions similar to those of human psoriasis. 106 Either neutralization of IL-17 or deletion of the Il17a gene ameliorates 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis in these mice. 106 In contrast to targeting IL-23 signaling, the inhibitory effects of targeting IL-17 signaling are less prominent in these animal models, indicating that alternative pathways may also contribute to the development of skin inflammation.…”

“…106 Either neutralization of IL-17 or deletion of the Il17a gene ameliorates 12-O-tetradecanoylphorbol-13-acetate-induced psoriasis in these mice. 106 In contrast to targeting IL-23 signaling, the inhibitory effects of targeting IL-17 signaling are less prominent in these animal models, indicating that alternative pathways may also contribute to the development of skin inflammation. 103,104,106 On a cellular level, IL-17 synergizes with other cytokines, such as TNFα, IFNγ or IL-22, to induce the production of proinflammatory cytokines, chemokines and antimicrobial peptides from keratinocytes.…”

IL12/IL23 Inhibition in the Treatment of Psoriatic Arthritis

“…Furthermore, IL23 has been shown to promote greater keratinocyte proliferation than IL12 [48]. In a phase I study, Nakajima et al showed that treatment of mice with psoriatic plaques with anti-IL23p19 antibodies greatly inhibited epidermal hyperplasia [49]. Based on these results, new humanized IgG monoclonal antibodies (BI655066 [50], guselkumab and tildrakizumab [51] formerly SCH900222 [52]), targeting the p19 subunit of IL23, were developed by several different companies and are currently in phase II clinical studies ( Table 2).…”

Paradoxical Role of IL-17 in Progression of Diabetic Nephropathy

“…Interestingly, loss of IL-17 has also been associated with disease susceptibility in part because it has been suggested that the absence of IL-17 results in enhanced production of other proinflammatory cytokines. 1 However, more recent studies have challenged the traditional pathogenic role of IL-17 as a purely proinflammatory cytokine. For instance, increased levels of IL-17 were shown to protect against autoimmune mediated type 1 diabetes in non-obese diabetic mice.…”