Rosacea is a chronic inflammatory cutaneous disease which mainly affects central face, leading to cosmetic disfigurement and compromised social psychology in billions of rosacea patients. Though the exact etiology of rosacea remains elusive, accumulating evidence has highlighted the dysfunction of innate immunity and inflammation in rosacea pathogenesis. Disintegrin Metalloprotease ADAM-like Decysin-1 (ADAMDEC1) is an orphan ADAM-like metalloprotease which is believed to be closely related to inflammation. Here for the first time, we reported that Adamdec1 expression was significantly increased in the skin lesions of rosacea patients and LL37-induced rosacea-like mouse models. Immunofluorescence analysis revealed co-localization of ADAMDEC1 and macrophages in patient and mouse biopsies. In cellular experiment, the expression of ADAMDEC1 was prominently elevated in M1 but not M2 macrophages. Knocking down of ADAMDEC1 significantly blunted M1 polarization in macrophages induced from human monocytes and THP-1 cell lines. Furthermore, silencing of Adamdec1 in LL-37-induced mouse model also suppressed the expression of M1 signature genes such as IL-6, iNOS and TNF-α, resulting in attenuated rosacea-like phenotype and inflammation. Taken together, our results demonstrate that ADAMDEC1 plays a pro-inflammatory role in rosacea via modulating the M1 polarization of macrophages.

Rosacea is a chronic skin disorder characterized by abnormal neurovascular and inflammatory conditions on the central face. Despite increasing evidence suggesting that rosacea is associated with metabolic disorders, the role of metabolism in rosacea pathogenesis remains unknown. Here, via a targeted metabolomics approach, we characterized significantly altered metabolic signatures in patients with rosacea, especially for amino acid-related metabolic pathways. Among these, glutamic acid and aspartic acid were highlighted and positively correlated with the disease severity in patients with rosacea. We further demonstrated that glutamic acid and aspartic acid can facilitate the development of erythema and telangiectasia, typical features of rosacea, in the skin of mice. Mechanistically, glutamic acid and aspartic acid stimulated the production of vasodilation-related neuropeptides from peripheral neurons and keratinocytes and induced the release of nitric oxide from endothelial cells and keratinocytes. Interestingly, we provided evidence showing that doxycycline can improve the symptoms of patients with rosacea possibly by targeting the amino acid metabolic pathway. These findings reveal that abnormal amino acid metabolism promotes neurovascular reactivity in rosacea and raise the possibility of targeting dysregulated metabolism as a promising strategy for clinical treatment.

Background: Rosacea is a common inflammatory skin disorder characterized by frequent facial flushing, erythema, telangiectasia, and papules, with a higher incidence observed in individuals aged 30−50 years and a tendency to decrease in the elderly. This age‐related decline in incidence drew our attention to further explore the relationship between rosacea pathogenesis and aging.Methods: We analyzed the incidence of rosacea across 8340 individuals without systemic diseases. The effects of LL37‐induced rosacea‐like erythema and inflammation were evaluated in both young and aged mice. Immunofluorescence analysis was performed to assess microvessel density, whereas the expression levels of angiogenesis‐related factors, including matrix metalloproteinases (MMPs) and vascular endothelial growth factor α (VEGFα), were quantified. Additionally, immune responses were assessed at both the cellular and systemic levels.Results: Aged mice displayed milder LL37‐induced rosacea‐like erythema and inflammation compared to their young counterparts. Immunofluorescence analysis revealed a decrease in microvessel density in rosacea models of the aged group. The expression of angiogenesis‐related factors, including MMPs and VEGFα, was decreased in aged mice compared to young mice, indicating a reduced responsiveness to LL37 stimulation. Furthermore, we found that suppressed Th1‐ and Th17‐polarized immune responses, one of the major pathogenic mechanisms of rosacea, were reduced in aged mice in response to LL37 stimulation at both cellular and systemic levels.Conclusion: The findings suggest that impaired angiogenesis and attenuated Th1/Th17 immune responses underlie the age‐related decline in rosacea incidence.