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  1. Article ; Online: Type I IFNs link skin-associated dysbiotic commensal bacteria to pathogenic inflammation and angiogenesis in rosacea

    Alessio Mylonas / Heike C. Hawerkamp / Yichen Wang / Jiaqi Chen / Francesco Messina / Olivier Demaria / Stephan Meller / Bernhard Homey / Jeremy Di Domizio / Lucia Mazzolai / Alain Hovnanian / Michel Gilliet / Curdin Conrad

    JCI Insight, Vol 8, Iss

    2023  Volume 4

    Abstract: Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with a high density of Bacillus oleronius and increased activity of kallikrein 5, which cleaves ...

    Abstract Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with a high density of Bacillus oleronius and increased activity of kallikrein 5, which cleaves cathelicidin antimicrobial peptide, are key pathogenic triggers in rosacea. However, how these events are linked to the disease remains unknown. Here, we show that type I IFNs produced by plasmacytoid DCs represent the pivotal link between dysbiosis, the aberrant immune response, and neovascularization. Compared with other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides, leading to enhanced generation of complexes with bacterial DNA. These bacterial DNA complexes but not DNA complexes derived from host cells are required for cathelicidin-induced activation of plasmacytoid DCs and type I IFN production. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I IFN–inducing capacities. In turn, excessive type I IFN expression drives neoangiogenesis via IL-22 induction and upregulation of the IL-22 receptor on endothelial cells. These findings unravel a potentially novel pathomechanism that directly links hallmarks of rosacea to the killing of dysbiotic commensal bacteria with induction of a pathogenic type I IFN–driven and IL-22–mediated angiogenesis.
    Keywords Dermatology ; Inflammation ; Medicine ; R
    Language English
    Publishing date 2023-02-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  2. Article ; Online: Differentiation of IL-26+ TH17 intermediates into IL-17A producers via epithelial crosstalk in psoriasis

    Anissa Fries / Fanny Saidoune / François Kuonen / Isabelle Dupanloup / Nadine Fournier / Ana Cristina Guerra de Souza / Muzlifah Haniffa / Feiyang Ma / Johann E. Gudjonsson / Lennart Roesner / Yang Li / Thomas Werfel / Curdin Conrad / Raphael Gottardo / Robert L. Modlin / Jeremy Di Domizio / Michel Gilliet

    Nature Communications, Vol 14, Iss 1, Pp 1-

    2023  Volume 14

    Abstract: Abstract Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic TH17 responses is unknown. Here we identify a population of blood TH17 intermediates ... ...

    Abstract Abstract Interleukin (IL)-26 is a TH17 cytokine with known antimicrobial and pro-inflammatory functions. However, the precise role of IL-26 in the context of pathogenic TH17 responses is unknown. Here we identify a population of blood TH17 intermediates that produce high levels of IL-26 and differentiate into IL-17A-producing TH17 cells upon TGF-β1 exposure. By combining single cell RNA sequencing, TCR sequencing and spatial transcriptomics we show that this process occurs in psoriatic skin. In fact, IL-26+ TH17 intermediates infiltrating psoriatic skin induce TGF-β1 expression in basal keratinocytes and thereby promote their own differentiation into IL-17A-producing cells. Thus, our study identifies IL-26-producing cells as an early differentiation stage of TH17 cells that infiltrates psoriatic skin and controls its own maturation into IL17A-producing TH17 cells, via epithelial crosstalk involving paracrine production of TGF-β1.
    Keywords Science ; Q
    Subject code 571
    Language English
    Publishing date 2023-06-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  3. Article ; Online: Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9

    Ernest Y. Lee / Changsheng Zhang / Jeremy Di Domizio / Fan Jin / Will Connell / Mandy Hung / Nicolas Malkoff / Veronica Veksler / Michel Gilliet / Pengyu Ren / Gerard C. L. Wong

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical ... ...

    Abstract Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Helical antimicrobial peptides assemble into protofibril scaffolds that present ordered dsDNA to TLR9

    Ernest Y. Lee / Changsheng Zhang / Jeremy Di Domizio / Fan Jin / Will Connell / Mandy Hung / Nicolas Malkoff / Veronica Veksler / Michel Gilliet / Pengyu Ren / Gerard C. L. Wong

    Nature Communications, Vol 10, Iss 1, Pp 1-

    2019  Volume 10

    Abstract: Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical ... ...

    Abstract Amphihelical antimicrobial peptides (AMPs) are bactericidal host defense factors, but their function as immunomodulators is emerging. Here the authors show that several AMPs organize DNA into periodic nanocrystals by self-assembling into superhelical protofibril scaffolds, which potentiates DNA sensing by TLR9.
    Keywords Science ; Q
    Language English
    Publishing date 2019-03-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  5. Article ; Online: IL-32γ potentiates tumor immunity in melanoma

    Thomas Gruber / Mirela Kremenovic / Hassan Sadozai / Nives Rombini / Lukas Baeriswyl / Fabienne Maibach / Robert L. Modlin / Michel Gilliet / Diego von Werdt / Robert E. Hunger / S. Morteza Seyed Jafari / Giulia Parisi / Gabriel Abril-Rodriguez / Antoni Ribas / Mirjam Schenk

    JCI Insight, Vol 5, Iss

    2020  Volume 18

    Abstract: Myeloid cells orchestrate the antitumor immune response and influence the efficacy of immune checkpoint blockade (ICB) therapies. We and others have previously shown that IL-32 mediates DC differentiation and macrophage activation. Here, we demonstrate ... ...

    Abstract Myeloid cells orchestrate the antitumor immune response and influence the efficacy of immune checkpoint blockade (ICB) therapies. We and others have previously shown that IL-32 mediates DC differentiation and macrophage activation. Here, we demonstrate that IL-32 expression in human melanoma positively correlates with overall survival, response to ICB, and an immune-inflamed tumor microenvironment (TME) enriched in mature DC, M1 macrophages, and CD8+ T cells. Treatment of B16F10 murine melanomas with IL-32 increased the frequencies of activated, tumor-specific CD8+ T cells, leading to the induction of systemic tumor immunity. Our mechanistic in vivo studies revealed a potentially novel role of IL-32 in activating intratumoral DC and macrophages to act in concert to prime CD8+ T cells and recruit them into the TME through CCL5. Thereby, IL-32 treatment reduced tumor growth and rendered ICB-resistant B16F10 tumors responsive to anti–PD-1 therapy without toxicity. Furthermore, increased baseline IL-32 gene expression was associated with response to nivolumab and pembrolizumab in 2 independent cohorts of patients with melanoma, implying that IL-32 is a predictive biomarker for anti–PD-1 therapy. Collectively, this study suggests IL-32 as a potent adjuvant in immunotherapy to enhance the efficacy of ICB in patients with non–T cell–inflamed TME.
    Keywords Immunology ; Oncology ; Medicine ; R
    Language English
    Publishing date 2020-09-01T00:00:00Z
    Publisher American Society for Clinical investigation
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  6. Article ; Online: TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis

    Curdin Conrad / Jeremy Di Domizio / Alessio Mylonas / Cyrine Belkhodja / Olivier Demaria / Alexander A. Navarini / Anne-Karine Lapointe / Lars E. French / Maxime Vernez / Michel Gilliet

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin ... ...

    Abstract The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.
    Keywords Science ; Q
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  7. Article ; Online: TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis

    Curdin Conrad / Jeremy Di Domizio / Alessio Mylonas / Cyrine Belkhodja / Olivier Demaria / Alexander A. Navarini / Anne-Karine Lapointe / Lars E. French / Maxime Vernez / Michel Gilliet

    Nature Communications, Vol 9, Iss 1, Pp 1-

    2018  Volume 11

    Abstract: The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin ... ...

    Abstract The pathogenesis of paradoxical psoriasis in patients receiving anti-TNF treatments for classical psoriasis is unclear. Here, the authors show that anti-TNF drugs enhance the production of type I interferon by plasmacytoid dendritic cells, causing skin lesions that, unlike classical psoriasis, lack T- cell autoimmunity.
    Keywords Science ; Q
    Language English
    Publishing date 2018-01-01T00:00:00Z
    Publisher Nature Publishing Group
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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    Inter-library loan at ZB MED

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  8. Article ; Online: Th17 micro-milieu regulates NLRP1-dependent caspase-5 activity in skin autoinflammation.

    Stephanie Zwicker / Eva Hattinger / Daniela Bureik / Aleksandra Batycka-Baran / Andreas Schmidt / Peter-Arne Gerber / Simon Rothenfusser / Michel Gilliet / Thomas Ruzicka / Ronald Wolf

    PLoS ONE, Vol 12, Iss 4, p e

    2017  Volume 0175153

    Abstract: IL-1β is a potent player in cutaneous inflammation and central for the development of a Th17 micro-milieu in autoinflammatory diseases including psoriasis. Its production is controlled at the transcriptional level and by subsequent posttranslational ... ...

    Abstract IL-1β is a potent player in cutaneous inflammation and central for the development of a Th17 micro-milieu in autoinflammatory diseases including psoriasis. Its production is controlled at the transcriptional level and by subsequent posttranslational processing via inflammatory caspases. In this study, we detected inflammatory caspase-5 active in epidermal keratinocytes and in psoriatic skin lesions. Further, interferon-γ and interleukin-17A synergistically induced caspase-5 expression in cultured keratinocytes, which was dependent on the antimicrobial peptide psoriasin (S100A7). However, diseases-relevant triggers for caspase-5 activity and IL-1β production remain unknown. Recently, extranuclear DNA has been identified as danger-signals abundant in the psoriatic epidermis. Here, we could demonstrate that cytosolic double-stranded (ds) DNA transfected into keratinocytes triggered the activation of caspase-5 and the release of IL-1β. Further, interleukin-17A promoted caspase-5 function via facilitation of the NLRP1-inflammasome. Anti-inflammatory vitamin D interfered with the IL-1β release and suppressed caspase-5 in keratinocytes and in psoriatic skin lesions. Our data link the disease-intrinsic danger signals psoriasin (S100A7) and dsDNA for NLPR1-dependent caspase-5 activity in psoriasis providing potential therapeutic targets in Th17-mediated skin autoinflammation.
    Keywords Medicine ; R ; Science ; Q
    Language English
    Publishing date 2017-01-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  9. Article ; Online: Generation of IL-23 producing dendritic cells (DCs) by airborne fungi regulates fungal pathogenicity via the induction of T(H)-17 responses.

    Georgios Chamilos / Dipyaman Ganguly / Roberto Lande / Josh Gregorio / Stephan Meller / William E Goldman / Michel Gilliet / Dimitrios P Kontoyiannis

    PLoS ONE, Vol 5, Iss 9, p e

    2010  Volume 12955

    Abstract: Interleukin-17 (IL-17) producing T helper cells (T(H)-17) comprise a newly recognized T cell subset with an emerging role in adaptive immunity to a variety of fungi. Whether different airborne fungi trigger a common signaling pathway for T(H)-17 ... ...

    Abstract Interleukin-17 (IL-17) producing T helper cells (T(H)-17) comprise a newly recognized T cell subset with an emerging role in adaptive immunity to a variety of fungi. Whether different airborne fungi trigger a common signaling pathway for T(H)-17 induction, and whether this ability is related to the inherent pathogenic behavior of each fungus is currently unknown. Here we show that, as opposed to primary pathogenic fungi (Histoplasma capsulatum), opportunistic fungal pathogens (Aspergillus and Rhizopus) trigger a common innate sensing pathway in human dendritic cells (DCs) that results in robust production of IL-23 and drives T(H)-17 responses. This response requires activation of dectin-1 by the fungal cell wall polysaccharide b-glucan that is selectively exposed during the invasive growth of opportunistic fungi. Notably, unmasking of b-glucan in the cell wall of a mutant of Histoplasma not only abrogates the pathogenicity of this fungus, but also triggers the induction of IL-23 producing DCs. Thus, b-glucan exposure in the fungal cell wall is essential for the induction of IL-23/T(H)-17 axis and may represent a key factor that regulates protective immunity to opportunistic but not pathogenic fungi.
    Keywords Medicine ; R ; Science ; Q
    Subject code 571
    Language English
    Publishing date 2010-09-01T00:00:00Z
    Publisher Public Library of Science (PLoS)
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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