Stephan Meller

Heinrich Heine University Düsseldorf

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Michel Gilliet

University of Lausanne

Bernhard Homey

Heinrich Heine University Düsseldorf

Dipyaman Ganguly

Indian Institute of Chemical Biology

Jérémy Di Domizio

University of Lausanne

Rüediger Liersch

Praxis für Hämatologie und Onkologie

Wei Cao

The University of Texas Health Science Center at Houston

Jens‐Michael Schröder

University Hospital Schleswig-Holstein

Max Bylesjö

Fios Genomics (United Kingdom)

Stephan Seeliger

University of Göttingen

Thomas K. Hoffmann

Universität Ulm

Cooperative Institutions

Heinrich Heine University Düsseldorf

Düsseldorf University Hospital

Karolinska Institutet

University of Helsinki

The University of Texas MD Anderson Cancer Center

King's College London

Inserm

The University of Texas Health Science Center at Houston

University Medical Center

Centre National de la Recherche Scientifique

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Generation of IL-23 Producing Dendritic Cells (DCs) by Airborne Fungi Regulates Fungal Pathogenicity via the Induction of TH-17 Responses

PLoS ONE (2010)

Georgios Chamilos Dipyaman Ganguly Roberto Lande Josh Gregorio Stephan Meller

Interleukin-17 (IL-17) producing T helper cells (TH-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 TH-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 TH-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/TH-17 axis and may represent a key factor that regulates protective immunity to opportunistic but not pathogenic fungi.

Histoplasma

Pathogenic fungus

10.1371/journal.pone.0012955

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Citations (121)

Microbe-host interplay in atopic dermatitis and psoriasis

Nature Communications (2019)

Nanna Fyhrquist Gareth Muirhead Stefanie Prast-Nielsen Marine Jeanmougin Péter Oláh

Abstract Despite recent advances in understanding microbial diversity in skin homeostasis, the relevance of microbial dysbiosis in inflammatory disease is poorly understood. Here we perform a comparative analysis of skin microbial communities coupled to global patterns of cutaneous gene expression in patients with atopic dermatitis or psoriasis. The skin microbiota is analysed by 16S amplicon or whole genome sequencing and the skin transcriptome by microarrays, followed by integration of the data layers. We find that atopic dermatitis and psoriasis can be classified by distinct microbes, which differ from healthy volunteers microbiome composition. Atopic dermatitis is dominated by a single microbe ( Staphylococcus aureus ), and associated with a disease relevant host transcriptomic signature enriched for skin barrier function, tryptophan metabolism and immune activation. In contrast, psoriasis is characterized by co-occurring communities of microbes with weak associations with disease related gene expression. Our work provides a basis for biomarker discovery and targeted therapies in skin dysbiosis.

Dysbiosis

10.1038/s41467-019-12253-y

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Citations (277)

Tumor immune escape by the loss of homeostatic chemokine expression

Proceedings of the National Academy of Sciences (2007)

Andor Pivarcsi Anja Müller Andreas Hippe Juliane Rieker Anke Van Lierop

The novel keratinocyte-specific chemokine CCL27 plays a critical role in the organization of skin-associated immune responses by regulating T cell homing under homeostatic and inflammatory conditions. Here we demonstrate that human keratinocyte-derived skin tumors may evade T cell-mediated antitumor immune responses by down-regulating the expression of CCL27 through the activation of epidermal growth factor receptor (EGFR)–Ras–MAPK-signaling pathways. Compared with healthy skin, CCL27 mRNA and protein expression was progressively lost in transformed keratinocytes of actinic keratoses and basal and squamous cell carcinomas. In vivo , precancerous skin lesions as well as cutaneous carcinomas showed significantly elevated levels of phosphorylated ERK compared with normal skin, suggesting the activation of EGFR–Ras signaling pathways in keratinocyte-derived malignancies. In vitro , exogenous stimulation of the EGFR–Ras signaling pathway through EGF or transfection of the dominant-active form of the Ras oncogene (H-RasV12) suppressed whereas an EGFR tyrosine kinase inhibitor increased CCL27 mRNA and protein production in keratinocytes. In mice, neutralization of CCL27 led to decreased leukocyte recruitment to cutaneous tumor sites and significantly enhanced primary tumor growth. Collectively, our data identify a mechanism of skin tumors to evade host antitumor immune responses.

10.1073/pnas.0705673104

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Citations (131)

Interleukin-26 activates macrophages and facilitates killing of Mycobacterium tuberculosis

Scientific Reports (2020)

Heike C. Hawerkamp Lasse van Geelen Jan Korte Jérémy Di Domizio Marc Swidergall

Abstract Tuberculosis-causing Mycobacterium tuberculosis (Mtb) is transmitted via airborne droplets followed by a primary infection of macrophages and dendritic cells. During the activation of host defence mechanisms also neutrophils and T helper 1 (T H 1) and T H 17 cells are recruited to the site of infection. The T H 17 cell-derived interleukin (IL)-17 in turn induces the cathelicidin LL37 which shows direct antimycobacterial effects. Here, we investigated the role of IL-26, a T H 1- and T H 17-associated cytokine that exhibits antimicrobial activity. We found that both IL-26 mRNA and protein are strongly increased in tuberculous lymph nodes. Furthermore, IL-26 is able to directly kill Mtb and decrease the infection rate in macrophages. Binding of IL-26 to lipoarabinomannan might be one important mechanism in extracellular killing of Mtb. Macrophages and dendritic cells respond to IL-26 with secretion of tumor necrosis factor (TNF)-α and chemokines such as CCL20, CXCL2 and CXCL8. In dendritic cells but not in macrophages cytokine induction by IL-26 is partly mediated via Toll like receptor (TLR) 2. Taken together, IL-26 strengthens the defense against Mtb in two ways: firstly, directly due to its antimycobacterial properties and secondly indirectly by activating innate immune mechanisms.

Antimycobacterial

CCL20

Lipoarabinomannan

10.1038/s41598-020-73989-y

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Nucleic acid-containing amyloid fibrils potently induce type I interferon and stimulate systemic autoimmunity

Proceedings of the National Academy of Sciences (2012)

Jérémy Di Domizio Stephanie Dorta‐Estremera Mihai Gagea Dipyaman Ganguly Stephan Meller

The immunopathophysiologic development of systemic autoimmunity involves numerous factors through complex mechanisms that are not fully understood. In systemic lupus erythematosus, type I IFN (IFN-I) produced by plasmacytoid dendritic cells (pDCs) critically promotes the autoimmunity through its pleiotropic effects on immune cells. However, the host-derived factors that enable abnormal IFN-I production and initial immune tolerance breakdown are largely unknown. Previously, we found that amyloid precursor proteins form amyloid fibrils in the presence of nucleic acids. Here we report that nucleic acid-containing amyloid fibrils can potently activate pDCs and enable IFN-I production in response to self-DNA, self-RNA, and dead cell debris. pDCs can take up DNA-containing amyloid fibrils, which are retained in the early endosomes to activate TLR9, leading to high IFNα/β production. In mice treated with DNA-containing amyloid fibrils, a rapid IFN response correlated with pDC infiltration and activation. Immunization of nonautoimmune mice with DNA-containing amyloid fibrils induced antinuclear serology against a panel of self-antigens. The mice exhibited positive proteinuria and deposited antibodies in their kidneys. Intriguingly, pDC depletion obstructed IFN-I response and selectively abolished autoantibody generation. Our study reveals an innate immune function of nucleic acid-containing amyloid fibrils and provides a potential link between compromised protein homeostasis and autoimmunity via a pDC-IFN axis.

Amyloid (mycology)

10.1073/pnas.1206923109

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Citations (54)