Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk

Tortola, Luigi; Rosenwald, Esther; Abel, Brian; Blumberg, Hal; Schäfer, Matthias; Coyle, Anthony J.; Renauld, Jean‐Christophe; Werner, Sabine; Kisielow, Jan; Köpf, Manfred

doi:10.1172/jci63451

Cited by 357 publications

(421 citation statements)

References 58 publications

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“…The potent proinflammatory activity of IL-36 cytokines also provides a possible explanation for the increased proliferation of keratinocytes that occurs in response to these cytokines in vivo (30,32,35), because immune cells produce various keratinocyte mitogens (36). In addition, we show in this article that IL-36g directly stimulates keratinocyte proliferation.…”

Section: Discussionmentioning

confidence: 58%

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Kurinna

Muzumdar

Köhler

et al. 2016

The Journal of Immunology

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The Nrf2 transcription factor is well known for its cytoprotective functions through regulation of genes involved in the detoxification of reactive oxygen species or toxic compounds. Therefore, activation of Nrf2 is a promising strategy for the protection of tissues from various types of insults and for cancer prevention. However, recent studies revealed a proinflammatory activity of activated Nrf2 and a stimulating effect on epithelial cell proliferation, but the underlying mechanisms of action and the responsible target genes are largely unknown. Using a combination of gene expression profiling, chromatin immunoprecipitation, and targeted proteomics via selected reaction monitoring, we show that the gene encoding the proinflammatory cytokine IL-36γ is a novel direct target of Nrf2 in keratinocytes and hepatocytes in vitro and in vivo. As a consequence, upregulation of IL-36γ expression occurred upon genetic or pharmacological activation of Nrf2 in the epidermis and in the normal and regenerating liver. Functional in vitro studies demonstrate that IL-36γ directly stimulates proliferation of keratinocytes. In particular, it induces expression of keratinocyte mitogens in fibroblasts, suggesting that the Nrf2–IL-36γ axis promotes keratinocyte proliferation through a double paracrine loop. These results provide mechanistic insight into Nrf2 action in the control of inflammation and cell proliferation through regulation of a proinflammatory cytokine with a key function in various inflammatory diseases.

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Section: Discussionmentioning

confidence: 58%

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Kurinna

Muzumdar

Köhler

et al. 2016

The Journal of Immunology

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“…Il17 –/– mice show significantly reduced severity in various inflammatory and autoimmune disease models, such as collagen‐induced arthritis,6 Il1rn −/− mouse arthritis,7 EAE8 and imiquimod (IMQ)‐induced skin inflammation,9, 10 suggesting critical roles of IL‐17 in inflammatory/autoimmune diseases. γδ 17 cells are detected in inflamed tissues of these disease models.…”

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

confidence: 99%

“…Mice deficient for IL‐17RA are highly susceptible to Klebsiella pneumoniae 3 and IL‐17‐deficient mice are susceptible to bacterial and fungal infection 4, 5. Interleukin‐17 is also implicated in various inflammatory/autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE), arthritis in IL‐1 receptor antagonist‐deficient (Il1rn –/– ) mice and imiquimod‐induced psoriatic dermatitis in mice 6, 7, 8, 9, 10. Anti‐IL‐17 and anti‐IL‐17RA antibodies are effective to treat patients with psoriasis and psoriatic arthritis 11, 12, 13.…”

Section: Introductionmentioning

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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“…There is now mounting evidence, from murine studies, that the IL-36R/IL-36α axis may have an important role in skin disorders [1][2][3]. This could also be the case in humans since missense mutations within IL-36RN genes, which encode for IL-36RA, an IL-36R antagonist, have been shown to be associated with pustular psoriasis [4].…”

Section: Introductionmentioning

confidence: 99%

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

et al. 2016

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We show that IL-36R is expressed by T (CD4+ and CD8+) and B (CD19+) lymphocytes in human blood and also by CD4+ T lymphocytes in the intestinal lamina propria. IL-36R protein was mostly stored in the cytoplasm of CD4 lymphocytes and B cells, during steady andthe greatest expression of IL-36R mRNA was measured in CD4+ (T helper) lymphocytesIL-36 β, which functions via IL-36R induced rapid and significant (P <0.05) proliferation of CD4+ lymphocytes, within 48h. IL-36R expression was also maintained on the surface of circulating CD4+ lymphocytes which enter the intestinal lamina propria.In conclusion our study is the first to show that (1) all human blood lymphocytes express IL-36R; (2) IL-36R expression is maintained by circulating CD4+ lymphocytes which enter the intestinal lamina propria and (3) IL-36R/IL-36 β induces rapid CD4 lymphocyte proliferation. The possible significance of these results in the context of human disease is discussed.3

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Psoriasiform dermatitis is driven by IL-36–mediated DC-keratinocyte crosstalk

Cited by 357 publications

References 58 publications

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

Autocrine and Paracrine Regulation of Keratinocyte Proliferation through a Novel Nrf2–IL-36γ Pathway

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

IL-36 receptor is expressed by human blood and intestinal T lymphocytes and is dose–dependently activated via IL-36β and induces CD4+ lymphocyte proliferation

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