IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells

Yoshiki, Ryutaro; Kabashima, Kenji; Honda, Tetsuya; Nakamizo, Satoshi; Sawada, Yu; Sugita, Kazunari; Yoshioka, Haruna; Ohmori, Shun; Malissen, Bernard; Tokura, Y.; Nakamura, Motonobu

doi:10.1038/jid.2014.98

Cited by 144 publications

(130 citation statements)

References 37 publications

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“…Van der Fits et al (7) and many others have provided solid evidence for a prominent role for the IL-23/IL-17 axis in psoriasis (35,51,52). Although the IL-17 cytokine family consists of multiple ligands, IL-17A is the most characterized ligand and is often referred to as IL-17.…”

Section: Discussionmentioning

confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease affecting 2–3% of the world population and is mainly characterized by epidermal hyperplasia, scaling, and erythema. A prominent role for TNF in the pathogenesis of psoriasis has been shown, and consequently various types of TNF antagonists such as etanercept and infliximab have been used successfully. Recently, increasing amounts of data suggest that type I IFNs are also crucial mediators of psoriasis. To investigate whether blocking their respective receptors would be useful, TNFR1- and IFNAR1-deficient mice were challenged with Aldara, which contains imiquimod, and is used as an experimental model to induce psoriasis-like skin lesions in mice. Both transgenic mice showed partial protection toward Aldara-induced inflammation compared with control groups. Additionally, TNFR1 knockout mice showed sustained type I IFN production in response to Aldara. Double knockout mice lacking both receptors showed superior protection to Aldara in comparison with the single knockout mice and displayed reduced levels of IL-12p40, IL-17F, and S100A8, indicating that the TNF and type I IFN pathways contribute significantly to inflammation upon treatment with Aldara. Our findings reveal that dual inhibition of TNFR1 and IFNAR1 may represent a potential novel strategic treatment of psoriasis.

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Section: Discussionmentioning

confidence: 99%

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Grine

Dejager

Libert

et al. 2015

The Journal of Immunology

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“…The function played by LCs in different mouse models of psoriasis-like inflammation has been controversial (14,38,39). A single study, based on DKO* mice, analyzed the late phase of psoriasis-like inflammation and suggested that LCs exert a negative immunoregulatory role via IL-10 and programmed cell death ligand-1 (7).…”

Section: Discussionmentioning

confidence: 99%

Dynamics and Transcriptomics of Skin Dendritic Cells and Macrophages in an Imiquimod-Induced, Biphasic Mouse Model of Psoriasis

Terhorst‐Molawi

Chelbi

Wohn

et al. 2015

The Journal of Immunology

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Psoriasis is a chronic inflammatory skin disease of unknown etiology. Previous studies showed that short-term, 5–7 d-long application of imiquimod (IMQ), a TLR7 agonist, to the skin of mice triggers a psoriasis-like inflammation. In the current study, by applying IMQ for 14 consecutive d, we established an improved mouse psoriasis-like model in that it recapitulated many of the clinical and cellular hallmarks observed in human patients during both the early-onset and the late-stable phase of psoriasis. Although macrophages and dendritic cells (DCs) have been proposed to drive the psoriatic cascade, their largely overlapping phenotype hampered studying their respective role. Based on our ability to discriminate Langerhans cells (LCs), conventional DCs, monocytes, monocyte-derived DCs, macrophages, and plasmacytoid DCs in the skin, we addressed their dynamics during both phases of our biphasic psoriasis-like model. Plasmacytoid DCs were not detectable during the whole course of IMQ treatment. During the early phase, neutrophils infiltrated the epidermis, whereas monocytes and monocyte-derived DCs were predominant in the dermis. During the late phase, LCs and macrophage numbers transiently increased in the epidermis and dermis, respectively. LC expansion resulted from local proliferation, a conclusion supported by global transcriptional analysis. Genetic depletion of LCs permitted to evaluate their function during both phases of the biphasic psoriasis-like model and demonstrated that their absence resulted in a late phase that is associated with enhanced neutrophil infiltration. Therefore, our data support an anti-inflammatory role of LCs during the course of psoriasis-like inflammation.

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“…The pathogenicity of γδ 17 cells in psoriasis is well studied in a mouse model of psoriasis, IMQ‐induced dermatitis 9, 23. Imiquimod is a Toll‐like receptor‐7/8 agonist and induces IL‐17‐dependent psoriasiform dermatitis by inducing IL‐23 63. The IMQ‐induced epidermal thickening is significantly decreased in Tcrd –/– mice, but not in Tcrb –/– mice 9.…”

Section: The Pathogenic Roles Of γδ17 Cells In Mouse Inflammatory Dismentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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IL-23 from Langerhans Cells Is Required for the Development of Imiquimod-Induced Psoriasis-Like Dermatitis by Induction of IL-17A-Producing γδ T Cells

Cited by 144 publications

References 37 publications

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

Dynamics and Transcriptomics of Skin Dendritic Cells and Macrophages in an Imiquimod-Induced, Biphasic Mouse Model of Psoriasis

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

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