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ResearchIn-Press PreviewDermatologyInflammation Open Access | 10.1172/jci.insight.151846

Type I interferons link skin-associated dysbiotic commensal bacteria to pathogenic inflammation and angiogenesis in rosacea

Alessio A. Mylonas,1 Heike C. Hawerkamp,2 Yichen Wang,3 Jiaqi Chen,1 Francesco Messina,1 Olivier Demaria,1 Stephan Meller,2 Bernhard Homey,2 Jeremy Di Domizio,1 Lucia Mazzolai,4 Alain Hovnanian,3 Michel Gilliet,1 and Curdin Conrad1

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

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1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

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1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

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1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Chen, J. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Messina, F. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Demaria, O. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Meller, S. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Homey, B. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Di Domizio, J. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Mazzolai, L. in: JCI | PubMed | Google Scholar

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Hovnanian, A. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Gilliet, M. in: JCI | PubMed | Google Scholar |

1Department of Dermatology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

2Department of Dermatology, Medical Faculty, Heinrich-Heine-University, Dusseldorf, Germany

3Department of Genetics, Université Paris Descartes, Sorbonne Paris-Cité, INSERM U781, Paris, France

4Department of Angiology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland

Find articles by Conrad, C. in: JCI | PubMed | Google Scholar

Published January 12, 2023 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.151846.
Copyright © 2023, Mylonas et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published January 12, 2023 - Version history
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Abstract

Rosacea is a common chronic inflammatory skin disease with a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. 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 interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, the aberrant immune response, and neovascularization. Compared to 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 dendritic cells and type I interferon production. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA-binding and type I interferon-inducing capacities. In turn, excessive type I interferon expression drives neoangiogenesis via IL22 induction and upregulation of the IL22 receptor on endothelial cells. These findings unravel a novel pathomechanism, which directly links hallmarks of rosacea to the killing of dysbiotic commensal bacteria with induction of a pathogenic type I interferon-driven and IL22-mediated angiogenesis.

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