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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
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
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Research Article Dermatology Inflammation

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

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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 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.

Authors

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

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Figure 8

Type I IFN cooperates with IL-22 in the induction of angiogenesis by promoting EC survival and proliferation.

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Type I IFN cooperates with IL-22 in the induction of angiogenesis by pro...
(A) The indicated cathelicidin peptides, or saline, were injected intradermally 4 times over a 48-hour period as previously, followed by intraperitoneal injection with BrdU for 72 hours. EC numbers were defined as Cd31+Cd45– cells from debris-excluded pregating, and they were determined per injection site. (B) Proliferation was determined by staining of Ki67 and BrdU from cells gated on ECs as in A, and defined as Ki67–single positive, Ki67-BrdU–double positive, and BrdU–single positive cells. (C) Mice intradermally injected with LL-37 or saline as in A and B were either pretreated with an anti-Ifnar blocking antibody or an IgG2a. EC numbers and proliferation were determined as in A and B. (D) HUVECs were plated (black bar at time of plating) and kept with or without growth factors (GFs) EGF, IGF1, FGF2, and VEGFA and with or without IL-22 or IL-17, in the presence or absence of IFN-α. Live cells were defined as CytoGreen+CytoXOrange– cells and depicted as absolute counts. (E) HUVEC were stimulated for 8 hours in the indicated conditions, and gene expression was analyzed for the designated genes. Results are representative of 3 independent experiments. (F) Mice were treated as in C and pretreated with an anti–IL-22 blocking antibody or an IgG2a, and EC counts and proliferation were assessed as in C. (G) Mice were treated as in C, with either an IgG2a, anti-Ifnar, or anti–IL-22 antibody, and vessels were visualized by videocapillaroscopy and counted in and around the injection site. Scale bar: 250 μm. Multiplicity adjusted P values of 1-way ANOVA are depicted in A, B, D, and G. P values of 2-tailed Mann-Whitney nonparametric unpaired t test are depicted in C and F.

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