Background: Rosacea is a chronic inflammatory skin disease with increased macrophage infiltration. However, the molecular mechanism remains unclear.Objectives: To determine the significance of macrophage infiltration, and the correlation between Guanylate‐binding protein 5 (GBP5) and polarization of macrophages in rosacea‐like inflammation.Methods: Here we tested the hypothesis that Guanylate‐binding protein 5 (GBP5) aggravates rosacea‐like skin inflammation by promoting the polarization of the M1 macrophages through the NF‐κB signalling pathway. We depleted macrophage by injecting clodronate‐containing liposomes. We next explored the association between GBP5 and macrophage in rosacea tissue through transcriptome analysis and immunofluorescence analysis. We evaluated the severity of rosacea‐like skin inflammation when BALB/c mice were injected with GBP5 siRNA intradermally daily for three consecutive days. At last, to study the causality of knocking down GBP5‐blunted M1 macrophage polarization, THP‐1 cell was treated with GBP5 siRNA.Results: Macrophage depletion ameliorated rosacea‐like skin inflammation in mice, implying the important role of macrophages in rosacea. Based on the transcriptome analysis, Guanylate‐binding protein 5 (GBP5) was identified as hub gene that was associated with macrophage infiltration in rosacea. Next, we found that GBP5 expression was significantly upregulated in rosacea tissues and positively correlated with macrophage infiltration, the immunofluorescence analysis revealed the co‐localization between GBP5 and macrophages. In vivo, silencing of GBP5 attenuated rosacea‐like skin inflammation in the LL‐37‐induced mouse model and suppressed the expression of M1 signature genes such as IL‐6, iNOS and TNF‐a. In vitro, knocking down GBP5 significantly blunted the polarization of the M1 macrophages partly by repressing the activation of the NF‐κB signalling pathways.Conclusions: Together, our study revealed the important role of macrophages in rosacea and identified GBP5 as a key regulator of rosacea by inducing M1 macrophage polarization via NF‐κB signalling pathways.

Background: Rosacea is a chronic inflammatory disease with variable clinical presentations, including transient flushing, fixed erythema, papules, pustules, and phymatous changes on the central face. Owing to the diversity in the clinical manifestations of rosacea, the lack of objective biochemical examinations, and nonspecificity in histopathological findings, accurate identification of rosacea is a big challenge. Artificial intelligence has emerged as a potential tool in the identification and evaluation of some skin diseases such as melanoma, basal cell carcinoma, and psoriasis. Objective: The objective of our study was to utilize a convolutional neural network (CNN) to differentiate the clinical photos of patients with rosacea (taken from 3 different angles) from those of patients with other skin diseases such as acne, seborrheic dermatitis, and eczema that could be easily confused with rosacea. Methods: In this study, 24,736 photos comprising of 18,647 photos of patients with rosacea and 6089 photos of patients with other skin diseases such as acne, facial seborrheic dermatitis, and eczema were included and analyzed by our CNN model based on ResNet-50. Results: The CNN in our study achieved an overall accuracy and precision of 0.914 and 0.898, with an area under the receiver operating characteristic curve of 0.972 for the detection of rosacea. The accuracy of classifying 3 subtypes of rosacea, that is, erythematotelangiectatic rosacea, papulopustular rosacea, and phymatous rosacea was 83.9%, 74.3%, and 80.0%, respectively. Moreover, the accuracy and precision of our CNN to distinguish rosacea from acne reached 0.931 and 0.893, respectively. For the differentiation between rosacea, seborrheic dermatitis, and eczema, the overall accuracy of our CNN was 0.757 and the precision was 0.667. Finally, by comparing the CNN diagnosis with the diagnoses by dermatologists of different expertise levels, we found that our CNN system is capable of identifying rosacea with a performance superior to that of resident doctors or attending physicians and comparable to that of experienced dermatologists. Conclusions: The findings of our study showed that by assessing clinical images, the CNN system in our study could identify rosacea with accuracy and precision comparable to that of an experienced dermatologist.

Rosacea is a chronic inflammatory disease in face. Hydroxychloroquine (HCQ), an anti-malaria drug, was reported to have anti-inflammation activities. However, the role of HCQ on rosacea remains unclear. In this study, we revealed the potential molecular mechanism by which HCQ improved rosacea in rosacea-like mice and mast cells (MCs). Moreover, the effects of HCQ treatment for rosacea patients were investigated. In this study, we found HCQ ameliorated the rosacea-like phenotype and MCs infiltration. The elevated pro-inflammatory factors and mast cell protease were significantly inhibited by HCQ treatment in rosacea-like mice. In vitro, HCQ suppresses LL37-induced MCs activation in vitro, including the release of inflammatory factors, chemotaxis, degranulation and calcium influx. Moreover, HCQ attenuated LL37-mediated MCs activation partly via inhibiting KCa3.1-mediated calcium signaling. Thus, these evidences suggest HCQ ameliorated rosacea-like dermatitis may be by regulating immune response of MCs. Finally, the 8-week HCQ treatment exerted satisfactory therapeutic effects on erythema and inflammatory lesions of rosacea patients, indicating that it is a promising drug for rosacea in clinical treatment.

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.