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

Germán, Beatriz; Wei, Ruicheng; Hener, Pierre; Martins, Christina; Ye, Tao; Gottwick, Cornelia; Yang, Jianying; Sénéschal, Julien; Boniface, Katia; Li, Mei

doi:10.1172/jci.insight.123390

Cited by 38 publications

(32 citation statements)

References 61 publications

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“…As shown in S1A Fig and previously reported [11,14], HDMECs expressed both IL-17RA and IL-1Rrp2 and this expression was not significantly influenced by IL-17A and IL-36γ, alone or in combination with TNF-α. Differently from IL-17 isoforms that are mainly produced by leukocytes, IL-36 cytokines are expressed by both HDMECs and keratinocytes [21,29]. HDMECs produced substantial amount of two of the three IL-36 isoforms with their release augmenting upon IL-17A or TNF-α stimulation and even more with their combination (S1B Fig).…”

Section: Resultsmentioning

confidence: 99%

“…induced by IL-17A, together with TNF-α, there are the IL-36 cytokines that, in turn, augment Th-17 functions, revealing the existence of a feedback loop able to amplify the IL-17 inflammatory signals [19]. IL-36 cytokines belong to the IL-1 family and are highly present in psoriasis, being produced by keratinocytes, macrophages and dendritic cells [20,21]. IL-36α, β and γ initiate a signal cascade that starts with binding to their IL-1Rrp2 receptor and leads to up-regulation of proinflammatory cytokines including IL-6 and CXCL-8/IL-8 [22].…”

Section: Introductionmentioning

confidence: 99%

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Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

et al. 2020

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In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A-and IL-36γ-dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocytederived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17Atreated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

et al. 2020

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“…These therapies were already used before molecular players of the disease were known. Recent studies show that these agents have an influence on the feedback loop between IL-36α or IL-36γ and the IL-23/IL-17 axis (92). It was shown in a murine psoriasis model that the vitamin D3 derivative calcipotriol inhibits the expression of IL-36α and IL-36γ in keratinocytes via their vitamin D receptor, which in turn prevents the infiltration of neutrophils (92) and saves skin from inflammation.…”

Section: Il-36 As a Therapeutic Targetmentioning

confidence: 99%

Interleukin-36 in Infectious and Inflammatory Skin Diseases

2019

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Interleukin-36 (IL-36) comprises to a cytokine family consisting of four isoforms IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36 Ra). These IL-36 cytokines, in turn, belong to the IL-1 superfamily. The IL-36 receptor (IL-1R6) is functional as a heterodimer formed of IL-1R6 and IL-1 receptor accessory protein (IL-1RAcP). IL-36α, IL-36β, and IL-36γ are regarded as pro-inflammatory ligands and IL-36 Ra as well as IL-38 as anti-inflammatory ligands of IL-1R6. IL-36 cytokines are mainly expressed on the barrier sites of the body e.g., bronchial, intestinal, and dermal epithelium. One of their most important biological functions is the bridging of innate and adaptive immune responses. A disturbed balance between pro-inflammatory and anti-inflammatory branches easily leads to inflammation of the corresponding tissue. The most prominent example for an altered IL-36 expression is the spectrum of psoriasis. In addition to inflammatory dermatoses, IL-36 also seems to play a role in infectious dermatoses. Microbial triggers, especially Staphylococcus aureus infection, increase the production of pro-inflammatory IL-36 cytokines and initiate/promote the inflammation of skin lesions. Due to the discovery of IL-36 as an important immune mediator, it has already been possible to develop important diagnostic tools for dermatitis. Not only in the field of inflammatory skin diseases, but also in pulmonary and intestinal inflammation, there is evidence that IL-36 cytokines might have diagnostic and/or therapeutic relevance.

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“…Concerning the regulation of the IL-36 family members by other cytokines, it seems that IL-22 and the Th17-related cytokines enhance the IL-36 expression within psoriatic lesions in murine models and human tissues [37], thus sustaining an autocrine and paracrine amplification loop between IL-36 and Th17 cytokines [37,47]. Interestingly, the anti-inflammatory effects of corticosteroids (e.g., dexamethasone) in mouse psoriatic skin are also driven by the disruption of the positive feedback loop between IL-36 and the Th17 axis [55]. Furthermore, the IL-36Ra deficiency exacerbates psoriasis in animal models [35] and the Deficiency of the interleukin-36 receptor antagonist (DITRA) is a recognized human syndrome characterized by generalized pustular psoriasis [56].…”

Section: Expression and Role Of Il-36 Cytokines In Inflamed Skin Amentioning

confidence: 99%

IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential

Boutet

Nerviani

Pitzalis

2019

IJMS

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The interleukin (IL)-1 family of cytokines is composed of 11 members, including the most recently discovered IL-36α, β, γ, IL-37, and IL-38. Similar to IL-1, IL-36 cytokines are initiators and amplifiers of inflammation, whereas both IL-37 and IL-38 display anti-inflammatory activities. A few studies have outlined the role played by these cytokines in several inflammatory diseases. For instance, IL-36 agonists seem to be relevant for the pathogenesis of skin psoriasis whereas, despite being expressed within the synovial tissue, their silencing or overexpression do not critically influence the course of arthritis in mice. In this review, we will focus on the state of the art of the molecular features and biological roles of IL-36, IL-37, and IL-38 in representative skin- and joint-related inflammatory diseases, namely psoriasis, rheumatoid arthritis, and psoriatic arthritis. We will then offer an overview of the therapeutic potential of targeting the IL-36 axis in these diseases, either by blocking the proinflammatory agonists or enhancing the physiologic inhibitory feedback on the inflammation mediated by the antagonists IL-37 and IL-38.

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

Cited by 38 publications

References 61 publications

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses

Interleukin-36 in Infectious and Inflammatory Skin Diseases

IL-36, IL-37, and IL-38 Cytokines in Skin and Joint Inflammation: A Comprehensive Review of Their Therapeutic Potential

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