Abstract
Rosacea is a common chronic inflammatory skin disease that is characterized by a fluctuating course of excessive inflammation and apparent neovascularization. Microbial dysbiosis with high density of B. oleronius and increased activity of the serine protease kallikrein 5, which cleaves cathelicidin antimicrobial peptide, have been recognized as key pathogenic triggers in rosacea. However, how these events are linked to the hallmarks of the disease remains unknown. Here, we show that type I interferons produced by plasmacytoid dendritic cells represent the pivotal link between dysbiosis, an aberrant immune response, and neovascularization in rosacea. In fact, compared to other commensal bacteria, B. oleronius is highly susceptible and preferentially killed by cathelicidin antimicrobial peptides leading to enhanced generation of complexes with DNA. DNA from skin-associated microbiota but not from host cells is required for cathelicidin-induced activation of plasmacytoid dendritic cells and type I-interferon production, which is further amplified by B. oleronius. Moreover, kallikrein 5 cleaves cathelicidin into peptides with heightened DNA binding and type I interferon-inducing capacities, further facilitating type I interferon production within the skin. In turn, type I interferons induce IL22 whilst simultaneously rendering endothelial cells responsive through upregulation of the IL22-receptor, and thereby driving drive neoangiogenesis. These findings unravel novel pathomechanisms, which directly link several hallmarks of rosacea to the killing of dysbiotic commensal bacteria and the induction of a pathogenic type-I interferon-TH17/22 pathway.
Wiskott-Aldrich syndrome protein–mediated actin dynamics control type-I interferon production in plasmacytoid dendritic cells