Original ArticleAnti-IL-17A and IL-23p19 antibodies but not anti-TNFα antibody induce expansion of regulatory T cells and restoration of their suppressive function in imiquimod-induced psoriasiform dermatitis
Introduction
Psoriasis is a common chronic inflammatory skin disease characterized by clinical features of erythematous and scaly plaques, and pathological features of aberrant hyperproliferation of keratinocytes and infiltration of neutrophils, affecting approximately 2–3% of the world’s population. A variety of cells such as keratinocytes, dendritic cells, Th1 cells, and Th17 cells are involved in the development of psoriasis and interact with each other through the production of cytokines [[1], [2], [3]]. The importance of the interleukin (IL)-17/IL-23 pathways in psoriasis pathogenesis has been proven by the efficacy of biologics targeting those cytokines such as IL-17A {ixekizumab [4] and secukinumab [5]}, IL-17RA {brodalumab [6]}, IL-12/23p40 {ustekinumab [7]}, IL-23p19 {guselkumab [8], risankizumab [9], and tildakizumab [10]}.
Aside from directly inhibiting key cytokines involved in psoriasis by biologics, other therapeutic approaches are available. Topical corticosteroid, topical vitamin D3, and UVB irradiation are effective for psoriasis. Among them, UVB therapy and topical vitamin D3 are assumed to exert their therapeutic effect not only through inhibiting T cell activation but also expanding regulatory T cells (Tregs) [[11], [12], [13]]. IL-10 has an anti-inflammatory effect, inhibiting the production of pro-inflammatory cytokines. It is produced by Treg lymphocytes in addition to macrophages, dendritic cells, and B lymphocytes [14]. Relative IL-10 deficiency in serum and skin in patients with psoriasis is an essential factor in pathogenesis [15]. Furthermore, dysfunction of Treg is significant in the pathogenesis of psoriasis [16]. Indeed, we recently demonstrated that the vitamin D3 analog, maxacalcitol, ameliorated imiquimod (IMQ)-induced psoriasiform skin inflammation on mice by inducing functional Tregs and suppressing IL-17 responses [17]. Additionally, previous clinical studies indicated that therapies such as UVB irradiation and topical vitamin D3 induced expansion of Tregs, which resulted in long-term remission [[18], [19], [20]]. However, the effect of IL-17 or IL-23 inhibition by antibodies on Treg function and expansion has not been clarified yet.
We previously reported that inhibition of tumor necrosis factor (TNF)-α [21] or IL-17A [22] by antibodies was effective for IMQ-induced psoriasiform skin inflammation on mice. However, we have not examined the detailed mechanism including the induction and function of Tregs. In this study, we investigated the effect of IL-17, IL-23 and TNF-α inhibition on the induction and function of Tregs using the IMQ-induced psoriasiform mouse model.
Section snippets
Mice
BALB/c mice were obtained from Sankyo Labo Service Corporation (Tokyo, Japan). All mice for experiments were 6- to 10-week-old females and were maintained in specific pathogen-free conditions at the animal facility of Teikyo University School of Medicine. This study was approved by the Animal Research Committee of Teikyo University School of Medicine (Number 17-015).
Reagents
Goat anti-mouse CD3ε (M-20) was obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Purified rat IgG2a,κ, biotinylated rat
Anti-TNFα, IL-17A and IL-23p19 mAbs reduced psoriasiform inflammation clinically and pathologically
Mean clinical severity scores and representative data at day 6 are shown in Fig. 1. There was no significant difference in the total clinical score among antibodies-injected mice without IMQ treatment (Fig. 1B). IMQ-treated mice and IMQ-treated mice injected with control IgG showed greatly increased scores in erythema, scaling and skin thickening as IMQ application was repeated, whereas anti-TNFα, IL-17A or IL-23p19 mAb-injected mice with IMQ application had significantly reduced increase in
Discussion
In this study, we demonstrated that administration of anti-TNFα, IL-17A or IL-23p19 mAb improved IMQ-induced psoriasis dermatitis in a mouse model clinically and histologically, through reduction of Th17-related cytokines expression, which is compatible with previous reports using other murine psoriasis model [21,22,26] and clinical data of biologics in human [[4], [5], [6], [7], [8],10].
Several papers reported that Tregs increased in peripheral blood or skin lesions in psoriasis [27,28], while
Funding source
This study was performed through joint research agreement between Teikyo University and Eli Lilly Japan K.K., with funding from Eli Lilly Japan K.K..
Declaration of Competing Interest
Dr Masahiro Kamata received grant for research from Torii Pharmaceutical, Eisai, Maruho, Novartis Pharma, and honoraria for lecture from Maruho, LEO Pharma, Eisai, AbbVie, Kyowa Hakko Kirin, Eli Lilly, Taiho Pharmaceutical, Mitsubishi Tanabe Pharma, and Janssen Pharmaceutical.
Dr Yayoi Tada received grant for research from Maruho, LEO Pharma, Eisai, AbbVie, Kyowa Hakko Kirin, Taiho Pharmaceutical, Celgene, and Eli Lilly, and honoraria for lectures from Maruho, LEO Pharma, Eisai, AbbVie, Kyowa
Acknowledgement
The authors wish to acknowledge Ms. Maiko Sakuragi for her assistance in performing some experiments.
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2022, Journal of Investigative DermatologyCitation Excerpt :The fact that in our patients, these Tregs are significantly increased only in the IL-12/23i‒treated group might reflect the fact that the biologics used by these patients may reverse the IL-23‒induced transition of Treg into pathogenic Th17 cells, resulting in an increase of Tregs. In line with our data, anti‒IL-23p19 antibody treatment in an imiquimod-induced psoriasis mouse model increased the number of Treg cells in the psoriatic lesions, and adoptive transfer of Tregs from anti‒IL-23p19 antibody‒treated mice improved psoriasis-like dermatitis in the donor mice (Shimizu et al., 2019). However, in a small study evaluating the T-cell immunophenotype in patients with psoriasis treated with ustekinumab, no significant differences have been found in CD4+CD127lowCD25highFoxp3+ from the controls, suggesting that what we observed in our patients might be specific for patients who develop candidiasis.
Apremilast downregulates interleukin-17 production and induces splenic regulatory B cells and regulatory T cells in imiquimod-induced psoriasiform dermatitis
2021, Journal of Dermatological ScienceCitation Excerpt :However, data on the in vivo effects of apremilast on the expression of key cytokines involved in psoriasis such as IL-17 and IL-10 are limited. In our study, we examined the in-vivo effect of apremilast on psoriasis, utilizing a commonly used murine model of imiquimod (IMQ)-induced psoriasiform skin inflammation [18–23]. BALB/c mice were obtained from Sankyo Labo Service Corporation (Tokyo, Japan).
Fingolimod ameliorates imiquimod-induced psoriasiform dermatitis by sequestrating interleukin-17-producing ?d T cells in secondary lymph nodes
2021, Journal of Dermatological ScienceCitation Excerpt :This mouse model was described as closely mimicking human psoriasis in both clinical and histological features, and has been used to explore the pathogenesis of psoriasis [25,26]. In fact, we previously reported that inhibition of IL-17A or IL-23 was effective in this mouse model as it was in human psoriasis patients [24,27]. In this study, we investigated the effect of fingolimod on psoriasis utilizing a mouse model of imiquimod-induced psoriasiform dermatitis, and explored the possibility of fingolimod as a therapeutic agent for psoriasis.
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