Rosacea is a common inflammatory skin disorder characterised by recurrent flare-ups and neoangiogenesis, eventually culminating in persistent erythema. Cathelicidin antimicrobial peptides and their upstream activating protease Kallikrein 5 (KLK5) have been implicated in rosacea, yet the pathogenic mechanisms that lead to flare-ups remain elusive. In gene expression analyses, we find selective overexpression of type I interferon (IFN) specifically during acute flare-ups of disease. Using an established in vivo model of rosacea, we find that IFN expression in situ, critically dependent on plasmacytoid dendritic cells (pDCs), drives a predominant TH17/22 profile, similar to the signature found in our patient cohort. Transgenic mice overexpressing KLK5 in the skin recapitulate the cathelicidin-pDC-IFN-TH17/22 axis, in support of a consistent overarching pathway. Finally, we find that IFN cooperates with IL22 to promote survival and proliferation of vascular endothelial cells, and in the sprouting of dermal microvasculature in vivo. Furthermore, B.oleronius, a bacterium that is linked to severity in rosacea, is exquisitely sensitive to killing by cathelicidins leading to potent activation of pDCs to produce IFN in vitro and in vivo. Taken together, proteolytic activation of cathelicidins, along with skin microbes lead to rapid pDC activation and IFN production during flare-ups of rosacea. The latter plays a critical role in inducing a predominant TH17/22 profile promoting pathogenic angiogenesis. Our study identifies a pathogenic KLK5-cathelicidin-pDC-IFN-IL22 axis in rosacea and mechanistically links B.oleronius to the induction of characteristic rosacea skin lesions, providing novel actionable targets for treatment along this pathway.

Type I interferon-driven pathogenic angiogenesis initiated by antimicrobial killing of B.oleronius during flare ups of rosacea