Interleukin-36–Receptor Antagonist Deficiency and Generalized Pustular Psoriasis

Marrakchi, Slaheddine; Guigue, Philippe; Renshaw, Blair R.; Puel, Anne; Pei, X.Y.; Fraïtag, Sylvie; Zribi, Jihen; Bal, Élodie; Cluzeau, Céline; Chrabieh, Maya; Towne, Jennifer E.; Douangpanya, Jason; Pons, Christian; Mansour, Sourour; Serre, Valérie; Makni, H.; Mahfoudh, N.; Fakhfakh, Faiza; Bodemer, Christine; Feingold, Josué; Hadj‐Rabia, Smail; Favre, Michel; Génin, Emmanuelle; Sahbatou, Mourad; Münnich, Arnold; Casanova, Jean‐Laurent; Sims, John E.; Turki, H.; Bachelez, Hervé; Smahi, Asma

doi:10.1056/nejmoa1013068

Cited by 858 publications

(935 citation statements)

References 32 publications

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“…IL-36 cytokines are overexpressed in affected skin of patients with inflammatory skin diseases, including atopic dermatitis and psoriasis (25)(26)(27)(28). The functional importance of this upregulation is supported by several recent findings: IL-36g mediates the alarmin function of the antimicrobial peptide LL37, and it functions as an alarmin that signals pathogen infections (20,29); injection of IL-36a promotes myeloid cell infiltration and their activation in the skin (30); tg mice overexpressing IL-36a in keratinocytes develop a psoriasis-like phenotype (31); the psoriasiform dermatitis that develops in mice after treatment with imiquimod depends on an IL-36-mediated cross-talk between dendritic cells and keratinocytes (32); and IL-36RA deficiency causes generalized pustular psoriasis in humans (33). Finally, a proinflammatory function of IL-36 cytokines in tissues other than the skin is emerging (34).…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…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]. In another study in which this association was made, peripheral blood mononuclear cells, isolated from these patients produced high concentrations of proinflammatory cytokines when cultured with IL-36α [5].…”

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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“…Although the mechanism of neutrophilic infiltration of bile ducts remains speculative, enhanced expression of interleukin-8 has been documented in cholangiocytes from lesion of neutrophilic cholangitis [6], in keratinocytes from skin lesions of psoriasis vulgaris and general psoriasis pustularis [2] and synovial lesions of psoriasis arthritis [7].…”

Section: Discussionmentioning

confidence: 99%

“…Psoriasis is a common chronic inflammatory skin disease affecting approximately 2% -3% of persons of European descent [2]. In the past decade many studies focused on comorbid conditions in psoriasis.…”

Section: Introductionmentioning

confidence: 99%

Cholangiosepsis Caused by Neutrophilic Cholangitis in Plaque Psoriasis

Bergthaler¹,

Kramer²,

Steiner³

et al. 2016

JCDSA

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Psoriasis is a common inflammatory skin disease with many comorbid conditions. We present a 37-year-old male patient with a history of plaque psoriasis, status febrilis, violent umbilical pain, elevated inflammatory markers and liver parameters. Blood cultures were tested positive for E. coli. Diagnostic findings indicated that mechanical icterus and cholangiosepsis in the context of neutrophilic cholangitis were caused by inflammatory stenosis. Neutrophilic cholangitis is often found in combination with skin diseases with intense cutaneous infiltration with polymorphonuclear leucocytes and peripherial blood neutrophilia. Interleukin-8 may play a role in the pathogenesis of neutrophilic cholangitis occurring in patients with psoriasis [1]. We showed that complications of psoriasis can also occur at unusual locations. To date no case of neutrophilic cholangitis as an elicitor of cholangiosepsis has been reported.

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Interleukin-36–Receptor Antagonist Deficiency and Generalized Pustular Psoriasis

Abstract: Aberrant interleukin-36Ra structure and function lead to unregulated secretion of inflammatory cytokines and generalized pustular psoriasis. (Funded by Agence Nationale de la Recherche and Société Française de Dermatologie.).

Cited by 858 publications

References 32 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

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

Cholangiosepsis Caused by Neutrophilic Cholangitis in Plaque Psoriasis

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