Original Article
Anti-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

https://doi.org/10.1016/j.jdermsci.2019.07.006Get rights and content

Highlights

  • Anti-TNFα, IL-17A and IL-23p19 antibodies (Ab) are effective for psoriasis.

  • However, the contribution of Treg in their effectiveness remains to be elucidated.

  • Anti-TNFα, IL-17A or IL-23p19 Ab ameliorated imiquimod-induced murine mouse model.

  • Anti-TNFα, IL-17A or IL-23p19 Ab downregulated Th17-related cytokines in psoriasis.

  • However, Anti-IL-17A and IL-23p19 Ab but not anti-TNFα Ab induces expansion of Tregs.

Abstract

Background

Psoriasis is a chronic inflammatory skin disease. Anti-TNFα, IL-17A and IL-23p19 antibodies are effective for psoriasis. However, the contribution of regulatory T cells (Treg) in their effectiveness remains to be elucidated.

Objective

We investigated the effects of TNFα, IL-17A and IL-23p19 inhibition on Tregs in imiquimod-induced psoriasiform dermatitis.

Methods

Psoriasiform dermatitis was induced by imiquimod application on murine shaved back skin for six days. Mice were treated with anti-TNFα, IL-17A or IL-23p19 monoclonal antibodies every other day from one day before imiquimod application.

Results

Administration of anti-TNFα, IL-17A or IL-23p19 antibodies improved the clinical score and downregulated Th17-related cytokines and chemokines, while IL-23p19 antibodies upregulated IL-10 mRNA expression. Anti-IL-17A or IL-23p19 antibody-treated imiquimod-applied mice showed a significant increase in the number of Foxp3+ IL-10+ Tregs. Recipient mice adoptively transferred with Tregs derived from donor mice treated with antibodies demonstrated clinical and pathological improvement in imiquimod-induced psoriasiform dermatitis. Anti-IL-17A or IL-23p19 antibody-induced Tregs significantly increased the number of Foxp3+ cells and IL-10 expression in imiquimod-induced psoriasiform dermatitis in recipient mice but anti-TNFα antibody-induced Tregs did not.

Conclusion

Anti-IL-17A or IL-23p19 antibody inhibits the IL-17/IL-23 signaling pathway, and induces expansion of Tregs and their suppressive capacity 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.

References (40)

  • L. Zhang et al.

    Increased Th17 cells are accompanied by FoxP3(+) Treg cell accumulation and correlated with psoriasis disease severity

    Clin. Immunol.

    (2010)
  • D.C. Soler et al.

    Psoriasis patients exhibit impairment of the high potency CCR5(+) T regulatory cell subset

    Clin. Immunol.

    (2013)
  • J.R. Maxwell et al.

    Differential Roles for Interleukin-23 and Interleukin-17 in Intestinal Immunoregulation

    Immunity

    (2015)
  • H.J. Koenen et al.

    Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells

    Blood

    (2008)
  • M. Tarique et al.

    IL-12 and IL-23 modulate plasticity of FoxP3(+) regulatory T cells in human Leprosy

    Mol. Immunol.

    (2017)
  • R.G. Langley et al.

    Psoriasis: epidemiology, clinical features, and quality of life

    Ann. Rheum. Dis.

    (2005)
  • R.G. Langley et al.

    Secukinumab in plaque psoriasis--results of two phase 3 trials

    N. Engl. J. Med.

    (2014)
  • M. Lebwohl et al.

    Phase 3 Studies Comparing Brodalumab with Ustekinumab in Psoriasis

    N. Engl. J. Med.

    (2015)
  • K.A. Papp et al.

    Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis

    N. Engl. J. Med.

    (2017)
  • K. Loser et al.

    Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells

    Nat. Med.

    (2006)
  • Cited by (23)

    • Immunological Effects of Anti‒IL-17/12/23 Therapy in Patients with Psoriasis Complicated by Candida Infections

      2022, Journal of Investigative Dermatology
      Citation 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 Science
      Citation 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 Science
      Citation 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.

    • Inhibition of interleukin-2-inducible T-cell kinase causes reduction in imiquimod-induced psoriasiform inflammation through reduction of Th17 cells and enhancement of Treg cells in mice

      2020, Biochimie
      Citation Excerpt :

      Our study showed downregulation of IL-17A in CD4+ T cells which could be linked with upregulation of Treg cells in ITK inhibitor treated psoriatic mice. An earlier study has shown that blocking IL-17A signaling during psoriatic inflammation in mice causes enhancement in Treg cells [56]. Elevation of Treg cells displays anti-inflammatory effects in skin of IMQ model [42,54].

    View all citing articles on Scopus
    View full text