interleukin-8 and Rosacea

Rosacea changes are a result of an immune mediated response and the angiogenic properties of the LL-37 peptide. This peptide induces an inflammatory signal that activates the NLRP3-mediated inflammasome, triggering rosacea pathogenesis. Research findings show that LL-37 peptide is inhibited by binding to a cell surface glycosaminoglycan, heparan sulfate. Heparan Sulfate Analog (HSA) is a proprietary low molecular weight analog of heparan sulfate that has been formulated into a Dermal Repair Cream (DRC), specifically to aid in such immune mediated responses. Herein, in vitro studies using human epidermal keratinocytes showed an increase in HSA decreased LL-37 toxicity and IL-8 cytokine release. A single-center, randomized double-blind trial included 16 subjects (Fitzpatrick skin types I-IV) with a clinical diagnosis of type 1 rosacea and moderate to severe facial erythema, who were undergoing Pulsed Dye Laser (PDL) treatment. The clinical improvements of their facial erythema were assessed at baseline, 2 weeks, 4 weeks, and 8 weeks. Results revealed that low molecular weight HSA significantly improves the clinical signs of rosacea during the 8 weeks of use likely resulting from inhibition of LL-37 induced IL-8 cytokine release. These findings support the use of DRC in rosacea topical treatment regimens as it demonstrates visible skin benefits and improves tolerability of PDL therapy in a shorter duration of time as compared with PDL alone.George R, Gallo RL, Cohen JL, et al. Reduction of erythema in moderate-severe rosacea by a low molecular weight Heparan Sulfate Analog (HSA). J Drugs Dermatol. 2023;22(6):546-553. doi:10.36849/JDD.7494.

Topics: Cathelicidins; Erythema; Heparitin Sulfate; Humans; Interleukin-8; Molecular Weight; Rosacea; Treatment Outcome

Rosacea is a common chronic inflammatory skin disease involving millions of patients worldwide. Previous studies have highlighted the upregulation of a variety of chemokines in the skin lesions of both rosacea patient and rosacea-like mouse model. However, the serum levels of these chemokines and their clinical significance have not been explored before. In this study, we aimed at examining the serum levels of a series of chemokines (including CCL2, CCL3, CCL20, CXCL1, CXCL8, CXCL9, CXCL10, and CXCL12) implicated in rosacea and their correlation with disease severity. Bio-Plex Pro Human Chemokine Assays were used to measure the serum levels of these chemokines. Investigator's Global Assessment (IGA) was applied for assessing the papules/pustules of rosacea patients, while persistent erythema was evaluated by the Clinician's Erythema Assessment (CEA). Our results revealed that the serum concentration of CCL3, CXCL8, CXCL9, and CXCL10 were markedly elevated in rosacea patients compared to healthy controls. Among them, the levels of CCL3, CXCL8, and CXCL9 were positively correlated with the IGA score, while serum CXCL9 and CXCL10 were positively related with the CEA score of rosacea patients. What's more, the expression of the corresponding receptors of CCL3 (Ccr1), CXCL8 (Cxcr1 and Cxcr2), CXCL9, and CXCL10 (Cxcr3) were all significantly increased in the skin lesions of rosacea-like mouse model with CXCR2 and CXCR3 highly expressed in rosacea patient skins. Our results indicated that CCL3, CXCL8, CXCL9, and CXCL10 might potentially serve as serum indicators for rosacea and could assist the severity evaluation of disease. Findings in this study would also potentially help to develop new targeted therapies for rosacea in future. © 2022 Japanese Dermatological Association.

Topics: Animals; Carcinoembryonic Antigen; Chemokine CCL3; Chemokine CXCL10; Chemokine CXCL9; Humans; Immunoglobulin A; Interleukin-8; Mice; Rosacea; Severity of Illness Index

The overexpression and increased activity of the serine protease Kallikrein 5 (KLK5) is characteristic of inflammatory skin diseases such as Rosacea. The use of inhibitors of this enzyme-such as 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF·HCl) or the anti-human recombinant Kallikrein 5 (anti-KLK5) antibody-in the treatment of the disease has been limited due to their low bioavailability, for which their immobilization in drug delivery agents can contribute to making serine protease inhibitors clinically useful. In this work, we synthesized gold nanoparticles (GNP) coated with a mixture of hydroxyl- and carboxyl-terminated thiolates (GNP.OH/COOH), whose carboxyl groups were used to further functionalize the nanoparticles with the serine protease inhibitor AEBSF·HCl either electrostatically or covalently (GNP.COOH AEBSF and GNP.AEBSF, respectively), or with the anti-KLK5 antibody (GNP.antiKLK5). The synthesized and functionalized GNP were highly water-soluble, and they were extensively characterized using UV-vis absorption spectroscopy, Transmission Electron Microscopy (TEM), Dynamic Light Scattering (DLS), and Thermogravimetric Analysis (TGA). GNP.OH/COOH and their subsequent functionalizations effectively inhibited KLK5 in vitro. Internalization of fluorophore-coated GNP.OH/COOH in human keratinocytes (HaCaT cells) was proven using confocal fluorescence microscopy. Cell viability assays revealed that the cytotoxicity of free AEBSF is importantly decreased when it is incorporated in the nanoparticles, either ionically (GNP.COOH AEBSF) or, most importantly, covalently (GNP.AEBSF). The functionalized nanoparticles GNP.AEBSF and GNP.antiKLK5 inhibited intracellular KLK5 activity in HaCaT cells and diminished secretion of IL-8 under inflammatory conditions triggered by TLR-2 ligands. This study points to the great potential of these GNP as a new intracellular delivery strategy for both small drugs and antibodies in the treatment of skin diseases such as Rosacea.

Topics: Antibodies; Cells, Cultured; Gold; Humans; Interleukin-8; Kallikreins; Metal Nanoparticles; Microscopy, Electron, Transmission; Microscopy, Fluorescence; Rosacea; Serine Proteinase Inhibitors; Solubility; Spectrophotometry, Ultraviolet; Sulfones; Thermogravimetry

Recently, the role of vasoactive peptides has been increasingly discussed in the pathogenesis of rosacea. The most attention is paid to the growth factor of the vascular endothelium (VEGF). VEGF affects angiogenesis and survival of immature blood vessels. Cytokine contributes to an increase in the level of IL-8, which plays a role in the development of inflammation. VEGF is synthesized by activated keratinocytes as a result of various factors. In particular, after exposure to ultraviolet irradiation, the production of cytokines-IL-1 and TNF-α-is provoced, which stimulate keratinocytes to synthesize of VEGF. The latest data on the state of the coagulation system in rosacea patients indicate a shift in the functional activity of the hemostasis system toward hypercoagulability. The aim of the study was to study the relationship between changes in the concentration of certain vasoactive peptides and the parameters of the hemostasis system in patients with rosacea. The state of the hemostasis system was assessed by prothrombin and thrombin time. The content of fibrinogen, fibrinolytic activity of blood, and also prothrombin index were determined as well. The concentration of free VEGF, IL-8 in the serum was determined by the method of enzyme immunoassay In the study, patients with rosacea, according to their age, were divided into 2 groups: -I group - patients aged 35 to 45 years, II group - patients aged 45 to 65 years. As the results of the study showed, the concentration of vasoactive peptides in patients with various clinical forms of rosacea differs significantly from those in the control group. In patients with various clinical forms of rosacea, the tendency of changes in all parameters (thrombin time, prothrombin time, fibrinogen, prothrombinic index) of the state of the coagulating system of blood with the manifestation of hypercoagulability is traced. And if the change in the content of cytokines was observed equally often in all observed patients, the manifestations of hypercoagulability were most pronounced in the second group of patients (aged 45 to 65 years) Thus, the results of the study allow us to conclude that an increase in the concentration of cytokines (which are a potent provoker of changes in permeability, atony and brittleness of the vessel walls), as well as hypercoagulable phenomena, indicative of ongoing microcracking processes, are the leading links in the pathogenesis of early forms of rosacea.

Topics: Adult; Age of Onset; Aged; Blood Coagulation; Case-Control Studies; Endothelium, Vascular; Female; Fibrinogen; Gene Expression Regulation; Humans; Interleukin-8; Male; Middle Aged; Prothrombin; Prothrombin Time; Rosacea; Signal Transduction; Vascular Endothelial Growth Factor A

In patients with rosacea, the monitoring of blood melatonin in the menopausal period, as one of the criteria for assessing the severity of the disease, seems appropriate and pathogenetically justified. The aim of this study was determination of blood melatonin, VEGF, IL-8 concentration in perimenopausal period of women suffering by rosacea. 43 to 65 years old 15 women with various clinical manifestations of rosacea, and severe climacteric syndrome were under observation. The control group consisted of 15 female patients with rosacea but without climacteric syndrome. Melatonin, VEGF,IL-8 level in serum were determined by ELISA (IBL - international - reagent), the results were expressed in pg/ml).As the results of the study showed, the concentration of vasoactive peptides in patients with rosacea differes significantly from those in the control group. Increase the concentration of cytokinesin in the blood of patients with rosacea indicate that they are playing significant role in the pathogenesis of rosaceaAccording to the results of the study, the concentration of melatonin was reduced in all patients with rosacea (the main group). The degree of reduction was in direct correlation with the severity of climacteric syndrome (11,6÷1,5 pg/ml at a rate of ≥ 20,0 pg/ml). In the control group, the melatonin concentration was approaching to the norm (19.1 pg/ml). Statistical analysis of received data revealed the correlation in between of the severity of dermatosis and changes in lipid metabolism and concentration of melatonin (R = 0,91; p <0,05) in the main group of patients (with rosacea and climacteric period). Thus, on the basis of the obtained results it can be concluded that the inclusion of melatonin-containing preparations in prescription for rosacea patients having climacteric syndrome pathogenetically is justified.

Topics: Adult; Aged; Case-Control Studies; Endothelial Growth Factors; Female; Humans; Interleukin-8; Melatonin; Middle Aged; Perimenopause; Rosacea

The purpose of the research was to study the lipid profile, some indices of hemostasis and cytokine status of rosacea patients with severe climacteric syndrome. Serum lipid profile was studied by means of the following parameters: total cholesterol, high density lipoproteins (HDL), low density lipoproteins (LDL), triglycerides (the study of lipid profile was performed by the device "INTEGRAM +400" (Company "ROSH»). Haemostatic system was evaluated in terms of prothrombin, thrombin time. Content of fibrinogen, fibrinolytic activity, and prothrombin index were determined. The concentration of free VEGF (vascular endothelial growth factor) and IL-8 were measured by ELISA. The results of these studies suggest that the phenomenon of hyper coagulation and disorders in lipid profile of blood serum in patients with rosacea with climacteric syndrome can be considered as risk factors of cardiovascular disease. From the other side, as a powerful provocateur of increased permeability, atony and fragility of vessel walls, VEGF, IL-2, IL-8 may be directly related to the mechanism of the development of cardiovascular disease in rosacea patients.

Topics: Aged; Blood Coagulation; Cardiovascular Diseases; Case-Control Studies; Female; Humans; Interleukin-8; Lipid Metabolism; Middle Aged; Postmenopause; Risk Factors; Rosacea; Severity of Illness Index; Syndrome; Vascular Endothelial Growth Factor A

The aim of this study is to quantify D. folliculorum colonisation in rosacea subtypes and age-matched controls and to determine the relationship between D. folliculorum load, rosacea subtype and skin innate immune system activation markers. We set up a multicentre, cross-sectional, prospective study in which 98 adults were included: 50 with facial rosacea, including 18 with erythematotelangiectatic rosacea (ETR), and 32 with papulopustular rosacea (PPR) and 48 age- and sex-matched healthy volunteers. Non-invasive facial samples were taken to quantify D. folliculorum infestation by quantitative PCR and evaluate inflammatory and immune markers. Analysis of the skin samples show that D. folliculorum was detected more frequently in rosacea patients than age-matched controls (96% vs 74%, P < 0.01). D. folliculorum density was 5.7 times higher in rosacea patients than in healthy volunteers. Skin sample analysis showed a higher expression of genes encoding pro-inflammatory cytokines (Il-8, Il-1b, TNF-a) and inflammasome-related genes (NALP-3 and CASP-1) in rosacea, especially PPR. Overexpression of LL-37 and VEGF, as well as CD45RO, MPO and CD163, was observed, indicating broad immune system activation in patients with rosacea. In conclusion, D. folliculorum density is highly increased in patients with rosacea, irrespective of rosacea subtype. There appears to be an inverse relationship between D. folliculorum density and inflammation markers in the skin of rosacea patients, with clear differences between rosacea subtypes.

Topics: Adult; Animals; Antimicrobial Cationic Peptides; Biomarkers; Case-Control Studies; Cathelicidins; Cyclooxygenase 2; Facial Dermatoses; Female; Gene Expression; Humans; Interleukin-1; Interleukin-8; Male; Mite Infestations; Mites; Polymerase Chain Reaction; Prospective Studies; Rosacea; Skin Diseases, Parasitic; Tumor Necrosis Factor-alpha

To correlate tear fluorescein clearance with interleukin-1alpha (IL-1alpha) concentration and gelatinase B (matrix metalloproteinase [MMP]-9) activity in the tear fluid of patients with ocular rosacea and normal control subjects.. Gelatinase activity was evaluated by gelatin zymography in tear fluid obtained from 13 patients with ocular rosacea (including 1 patient with recurrent epithelial erosion, 2 with recurrent peripheral corneal infiltrates and vascularization, and 2 patients with epithelial basement membrane dystrophy) and 13 normal subjects with normal aqueous tear production and no irritation symptoms. Tear fluorescein clearance was evaluated by measuring fluorescence in tear fluid collected from the inferior meniscus 15 minutes after instillation of 5 microl of 2% Na-fluorescein with a CytoFluor II fluorometer. Pro-MMP-9 and IL-1alpha concentrations in the tear fluid were measured by enzyme-linked immunosorbent assay (ELISA).. Compared with normal control subjects, patients with ocular rosacea had a greater delay of tear fluorescein clearance (P < 0.001), a higher tear IL-1alpha concentration (P < 0.001), and a greater pro-gelatinase B (92 kDa) activity (P < 0.001) in their tear fluid. The 84-kDa active form of gelatinase B was observed in 46% of the rosacea tear samples and none of the controls. The zymographic results were confirmed by ELISA that showed a significantly greater concentration of pro-MMP-9 (92 kDa) in the tear fluid of rosacea patients than controls. Delayed tear clearance was correlated with elevated tear IL-1alpha concentration (p=0.67, P < 0.001) and increased tear gelatinase B activity (p=0.84, P < 0.001). Tear IL-1alpha concentration was correlated with tear gelatinase B activity (p=0.58, P < 0.002).. Gelatinase B (MMP-9) activity is greater in patients with ocular rosacea than in normal eyes. The majority of this activity is due to 92-kDa proform of this enzyme. This activity is correlated with delayed tear clearance and tear fluid concentration of interleukin-1alpha, a proinflammatory cytokine that has been reported to stimulate gelatinase B production. Elevated gelatinase B activity in ocular rosacea may be involved in the pathogenesis of the irritation symptoms, recurrent epithelial erosions, vascularization, and epithelial basement membrane dystrophy that develops in the corneas of patients with this condition.

Topics: Adult; Aged; Aged, 80 and over; Collagenases; Conjunctival Diseases; Corneal Diseases; Enzyme-Linked Immunosorbent Assay; Female; Fluorescein; Fluorophotometry; Humans; Interleukin-8; Male; Matrix Metalloproteinase 9; Middle Aged; Rosacea; Tears