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: The role of M0 macrophages and their related genes in the prognosis of hepatocellular carcinoma (HCC) remains poorly characterized. Methods: Multidimensional bioinformatic methods were used to construct a risk score model using M0 macrophage-related genes (M0RGs). Results: Infiltration of M0 macrophages was significantly higher in HCC tissues than in normal liver tissues (P = 2.299e-07). Further analysis revealed 35 M0RGs that were associated with HCC prognosis; two M0RGs (OLA1 and ATIC) were constructed and validated as a prognostic signature for overall survival of patients with HCC. Survival analysis revealed the positive relationship between the M0RG signature and unfavorable prognosis. Correlation analysis showed that this risk model had positive associations with clinicopathological characteristics, somatic gene mutations, immune cell infiltration, immune checkpoint inhibitor targets, and efficacy of common drugs. Conclusions: The constructed M0RG-based risk model may be promising for the clinical prediction of prognoses and therapeutic responses in patients with HCC.

Rosacea is significantly associated with dementia, particularly Alzheimer’s disease (AD). However, the common underlying molecular mechanism connecting these two diseases remains limited. This study aimed to reveal the common molecular regulatory networks and identify the potential therapeutic drugs for rosacea and AD. There were 747 overlapped DEGs (ol-DEGs) that were detected in AD and rosacea, enriched in inflammation-, metabolism-, and apoptosis-related pathways. Using the TF regulatory network analysis, 37 common TFs and target genes were identified as hub genes. They were used to predict the therapeutic drugs for rosacea and AD using the DGIdb/CMap database. Among the 113 predicted drugs, melatonin (MLT) was co-associated with both RORA and IFN-γ in AD and rosacea. Subsequently, network pharmacology analysis identified 19 pharmacological targets of MLT and demonstrated that MLT could help in treating AD/rosacea partly by modulating inflammatory and vascular signaling pathways. Finally, we verified the therapeutic role and mechanism of MLT on rosacea in vivo and in vitro. We found that MLT treatment significantly improved rosacea-like skin lesion by reducing keratinocyte-mediated inflammatory cytokine secretion and repressing the migration of HUVEC cells. In conclusion, this study contributes to common pathologies shared by rosacea and AD and identified MLT as an effective treatment strategy for rosacea and AD via regulating inflammation and angiogenesis.

Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and vascular system. Artemisinin (ART), an anti-malaria drug, was reported to have several effects including anti-inflammation and anti-angiogenesis activities. However, the role of ART on rosacea remains unclear. To investigate the effects and molecular mechanism of ART on rosacea. In rosacea-like mouse model, the phenotype of rosacea lesions was evaluated by redness score, the inflammatory biomarkers were analyzed by qPCR, and the infiltration of inflammatory cells were assessed by IHC analysis and immunofluorescence. In vitro, LL37-induced expression of inflammatory factors in HaCaT cells was detected by qPCR, potential signaling pathways were detected by Western blotting or immunofluorescence. Migration ability of human umbilical vein endothelial cells (HUVECs) was evaluated by cell scratch and transwell assays. The skin erythema and histopathological alteration, as well as the elevated pro-inflammatory factors (IL-1β, IL6, TNFα) and TLR2 were significantly ameliorated by ART treatment in LL37-induced rosacea-like mice. In addition, ART reduced the infiltration of CD4⁺ T cells, macrophages and neutrophils, and repressed the expression of immune cells related chemokines (CXCL10, CCL20, CCL2 and CXCL2) in mouse lesions. In HaCaT cells, ART significantly decreased the LL37-induced expression of inflammatory biomarkers. Moreover, we found that ART inhibited rosacea-like inflammation via NF-kB signaling pathways in HaCaT cells. Finally, for vascular dysregulation, ART repressed the angiogenesis in mouse model and inhibited the LL37-induced HUVECs migration in vitro. ART ameliorated rosacea-like dermatitis by regulating immune response and angiogenesis, indicating that it could represent an effective therapeutic option for patients with rosacea.

Reactive oxygen species (ROS)-activated proinflammatory signals in keratinocytes play a crucial role in the immunoregulation of inflammatory skin diseases, including rosacea and psoriasis. Nav1.8 is a voltage-gated sodium ion channel, and its abnormal expression in the epidermal layer contributes to pain hypersensitivity in the skin. However, whether and how epidermal Nav1.8 is involved in skin immunoregulation remains unclear. This study was performed to identify the therapeutic role of Nav1.8 in inflammatory skin disorders. We found that Nav1.8 expression was significantly upregulated in the epidermis of rosacea and psoriasis skin lesions. Nav1.8 knockdown ameliorated skin inflammation in LL37-and imiquimod-induced inflammation mouse models. Transcriptome sequencing results indicated that Nav1.8 regulated the expression of pro-inflammatory mediators (IL1β and IL6) in keratinocytes, thereby contributing to immune infiltration in inflammatory skin disorders. In vitro, tumor necrosis factor alpha (TNFα), a cytokine that drives the development of various inflammatory skin disorders, increased Nav1.8 expression in keratinocytes. Knockdown of Nav1.8 eliminated excess ROS production, thereby attenuating the TNFα-induced production of inflammatory mediators; however, a Nav1.8 blocker did not have the same effect. Mechanistically, Nav1.8 reduced superoxide dismutase 2 (SOD2) activity by directly binding to SOD2 to prevent its deacetylation and mitochondrial localization, subsequently inducing ROS accumulation. Collectively, our study describes a central role for Nav1.8 in regulating pro-inflammatory responses in the skin and indicates a novel therapeutic strategy for rosacea and psoriasis.