Inhibition of IL-17–committed T cells in a murine psoriasis model by a vitamin D analogue

Kusuba, Nobuhiro; Kitoh, Akihiko; Dainichi, Teruki; Honda, Tetsuya; Otsuka, Atsushi; Egawa, Gyohei; Nakajima, Saeko; Kabashima, Kenji

doi:10.1016/j.jaci.2017.07.033

Cited by 27 publications

(39 citation statements)

References 80 publications

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“…Although recent developments and success in the use of biologic therapies highlighted that immune regulation plays a vital role in the development of psoriasis, there is also cumulative evidence that www.nature.com/scientificreports www.nature.com/scientificreports/ interaction of epidermal factors and the immune system play a synergistic role in the initiation and maintenance of disease. Since clinical studies have practical and ethical limitations, conventional 2D culture and animal models have been widely utilized [41][42][43][44][45][46][47] . A large body of previous research focused on developing 3D in vitro psoriasis models, which can mimic psoriasis pathophysiology [14][15][16][17][18][19]48,49 .…”

Section: Discussionmentioning

confidence: 99%

Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing

Shin

Abaci

Herron

et al. 2020

Sci Rep

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Drug screening studies for inflammatory skin diseases are currently performed using model systems that only partially recapitulate human diseased skin. Here, we developed a new strategy to incorporate T cells into human 3D skin constructs (HSCs), which enabled us to closely monitor and quantitate T cell responses. We found that the epidermis promotes the activation and infiltration of T cells into the skin, and provides a directional cue for their selective migration towards the epidermis. We established a psoriatic HSC (pHSC) by incorporating polarized Th1/Th17 cells or CCR6+CLA+ T cells derived from psoriasis patients into the constructs. These pHSCs showed a psoriatic epidermal phenotype and characteristic cytokine profiles, and responded to various classes of psoriasis drugs, highlighting the potential utility of our model as a drug screening platform. Taken together, we developed an advanced immunocompetent 3D skin model to investigate epidermal-T cell interactions and to understand the pathophysiology of inflammatory skin diseases in a human-relevant and patient-specific context.Skin is equipped with a complex immune system that involves various immune cell types, such as T cells, Langerhans cells, dermal dendritic cells, mast cells, and basophils, which secrete cytokines and chemokines to regulate immune responses both locally and systemically. Perturbations in this complex regulatory mechanism due to genetic and/or environmental factors contribute to the development of inflammatory skin diseases 1 . Therefore, understanding the skin immune system is essential to investigate the pathogenesis of inflammatory skin diseases and to discover and validate effective targets for treatment.Psoriasis affects 2-3% of the Western population 2,3 and is a chronic inflammatory skin disease with dysregulated keratinocyte proliferation 4 . In the pathogenesis of psoriasis, the interplay between keratinocytes and immune cells is important for the initiation, progression and persistence of the disease. Psoriatic keratinocytes recruit and activate plasmacytoid dendritic cells and neutrophils to initiate psoriasis 5-8 , and produce autoantigens, such as LL37 5-7 , ADAMTSL5 9 , and PLA2G4D 10 to activate T cells. Once T cells and DCs are recruited and activated, a cytokine niche is established including IFNs, IL-17, TNFα, and IL-22 11-13 . These cytokines not only alter epidermal proliferation and differentiation 12,13 , but also activate keratinocytes to release chemokines and chemoattractants, which induce further recruitment and infiltration of inflammatory cells into the skin 11 . Although this complex feedback loop between keratinocytes and immune cells is central in the pathogenesis of psoriasis, current in vitro models do not capture these cellular interactions, such as migration of the immune cells, highlighting the need for an advanced model that recapitulates the physiological and immunological complexity of the disease.Although there have been improvements in the efficacy of biologic therapies, therapeutic outcomes v...

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Section: Discussionmentioning

confidence: 99%

Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing

Shin

Abaci

Herron

et al. 2020

Sci Rep

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“…For example, it was shown that Cal acted on DCs and T cells in ex vivo-cultured human psoriatic skin explants to inhibit IL-23 and IL-17 expression, respectively (26). More recently, it was reported that Cal suppressed the IL-23 expression by epidermal LCs, which was assumed to be the reason for the inhibition of IL-17 by Cal in Ald-induced mouse psoriasis (27). In our study, we showed that the inhibition of IL-23/IL-17/IL-22 by Cal was abolished in Vdr KC-/-(mice with the ablation of VDR selectively in KCs) ( Figure 2, A and B), which demonstrates that this inhibiting effect is actually dependent on keratinocytic VDR.…”

Section: Discussionmentioning

confidence: 99%

“…This has led us to uncover a mechanism showing that Cal acts on KCs instead of immune cells (such as T cells, DCs, or Langerhans cells [LCs]; refs. 26,27) to suppress the IL-23/IL-17 inflammatory axis in psoriasis and, furthermore, to provide evidence about how the combination of Cal and dexamethasone (Dex) effectively disrupt the positive cytokine feedback loop of IL-36 and IL-23/IL-17, which we believe underlies the superior efficacy of the combination therapy for psoriasis.…”

Section: Introductionmentioning

confidence: 99%

Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis

Germán¹,

Wei²,

Hener³

et al. 2019

JCI Insight

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“…The so‐called biologics that target TNFα (etanercept, infliximab, adalimumab), IL12/23 (ustekinumab) and IL‐17 (secukinumab, ixikizumab) and small molecules targeting the downstream JAK‐STAT pathway (tofacitinib) are effective treatments for moderate to severe psoriasis patients. Still, current research on therapeutics for psoriasis is greatly facilitated by animal models developed to mimic human psoriasis disease . Although the field has advanced considerably, and the biologics changed the lives of many psoriasis patients, there is still an unmet need for newly developed drugs and identification of drug targets in the treatment of psoriasis.…”

Section: Psoriasis: From Disease Pathogenesis To Disease Hallmarks Mmentioning

confidence: 99%

“…Still, current research on therapeutics for psoriasis is greatly facilitated by animal models developed to mimic human psoriasis disease. [27][28][29] Although the field has advanced considerably, and the biologics changed the lives of many psoriasis patients, there is still an unmet need for newly developed drugs and identification of drug targets in the treatment of psoriasis. In-depth knowledge on the disease pathogenesis, in part facilitated by in vitro skin models, will facilitate future drug development studies.…”

Section: Immune Cells and Cytokinesmentioning

confidence: 99%

Past, present and future of in vitro 3D reconstructed inflammatory skin models to study psoriasis

Niehues

Bogaard

2018

Experimental Dermatology

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Psoriasis is a common chronic inflammatory disease affecting about 1%-2% of today's Western population.[1] Several subtypes of psoriasis are known, but herein we focus on psoriasis vulgaris which is most prevalent and phenotypically characterized by sharply demarcated plaques covered with white scales. The pathogenesis of psoriasis is complex and exact mechanisms of disease onset and manifestation remain unknown. However, it is known that psoriasis cannot be attributed to a single risk factor or insult but is likely caused by the interaction of environmental and genetic factors. Based on a number of genomewide association studies (GWAS) and meta-analyses thereof, more than 60 susceptibility loci have been identified that account for 20%-25% of psoriasis heritability. [2][3][4][5][6][7] Although psoriasis has been regarded as an (auto) immune disease for a long time, an increasing body of evidence directs towards a combined role for the innate and adaptive immune system in combination with tissue specific epidermal factors. AbstractPsoriasis is a common chronic inflammatory skin disease with a significant socioeconomic impact that can greatly affect the patients' quality of life. The prevailing dogma in the aetiology and pathophysiology of this complex disease is that skin cells, immune cells and environmental factors contribute to psoriatic skin inflammation.For a better understanding of the disease pathogenesis, models are required that mimic the disease and which can be used to develop therapeutics. Over the last decades, in vitro human reconstructed skin models have been widely used in dermatological research and have also been developed to mimic psoriatic skin. This viewpoint summarizes the most commonly used in vitro models and the latest accomplishments for the combination of the dermal and epidermal compartments with other cell types

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Inhibition of IL-17–committed T cells in a murine psoriasis model by a vitamin D analogue

Abstract: Topical CAL can exert its antipsoriatic effect on CAL-treated lesions and, concomitantly, distant lesions by attenuating the T17 cell accumulation in both CAL-treated lesions and draining lymph nodes.

Cited by 27 publications

References 80 publications

Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing

Recapitulating T cell infiltration in 3D psoriatic skin models for patient-specific drug testing

Disrupting the IL-36 and IL-23/IL-17 loop underlies the efficacy of calcipotriol and corticosteroid therapy for psoriasis

Past, present and future of in vitro 3D reconstructed inflammatory skin models to study psoriasis

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