Dermal Inflammatory Cell Research Articles

Understanding host's response to staphylococcal scalded skinsyndrome.

The aim of this review was to summarise the current knowledge on host-related factors that contribute to the development and severity of staphylococcal scalded skin syndrome (SSSS) in children. A comprehensive assessment and analysis of the existing literature on SSSS clinical features, pathogenesis and susceptibility factors. SSSS is a blistering skin disease caused by circulating exfoliative toxins (ETs) of Staphylococcus aureus (S. aureus), almost exclusively affecting infants, young children and immunocompromised individuals. ETs possess serine protease activity and target desmoglein-1 (Dsg-1) in the superficial epidermis. While the role of S. aureus ETs and site of action are well-described, other host factors such as impaired immune responses to ETs, poor renal clearance and genetic factors are crucial for the onset of and/or the severity of SSSS in children. The fate of desmosomal fractions after cleavage by ETs, as well as the role of dermal inflammatory cell infiltrates remain to be elucidated.

Comprehensive analysis of Hibisci mutabilis Folium extract's mechanisms in alleviating UV-induced skin photoaging through enhanced network pharmacology and experimental validation.

Skin photoaging induced by ultraviolet A (UVA) and ultraviolet B (UVB) radiation manifests as skin roughness, desquamation, pigmentation, and wrinkle formation. Current treatments, such as sunscreen, hormones, and antioxidants, have limitations and side effects. Traditional Chinese Medicine Hibisci Mutabilis Folium (HMF), or Mu-Fu-Rong-Ye in Chinese name, refers to the dried leaves of the plant Hibiscus mutabilis L., which belongs to the Malvaceae family. It has been used traditionally to treat acute mastitis, parotitis, neurodermatitis, burns. The reported activities of HMF include anti-inflammatory and anti-oxidant effects. However, the therapeutic potential of HMF in preventing and treating UV-induced skin photoaging remains unexplored. This study aimed to investigate the protective effects of HMF extract (EHMF) against UV-induced skin photoaging and the underlying mechanisms of action, by using network pharmacology and experimental verification. Network pharmacology was employed to identify the effective chemical components of EHMF. Potential targets were identified via PPI network analysis. Representative compounds were characterized using UPLC-MS/MS. In vitro validation involved assessing HaCaT cell viability, observing live/dead cell staining through fluorescence microscopy, and measuring inflammatory factors using ELISA. For in vivo validation, a UV-induced skin photoaging mice model was treated transdermally with EHMF or Methotrexate daily for 7 days. Dermatitis severity, skin morphology, and collagen fiber pathology were evaluated. Inflammatory cytokine and protein expression in dorsal skin lesions was confirmed using Elisa Kits, Western blot and immunohistochemistry. A total of 22 active ingredients of EHMF were identified. GO enrichment and KEGG pathway analyses revealed a focus on inflammatory signaling pathways. In vitro experiments showed that EHMF significantly reduced UV-induced inflammatory factors in HaCaT cells and improved cell survival rates. In vivo, EHMF alleviated back skin lesions in UV-exposed mice, reducing epidermal and dermal thickening and pathological inflammatory cell infiltration. It also decreased abnormal MMP-9 expression and collagen fiber proliferation, along with levels of inflammatory factors like TNF-α, IL-6, IL-17, and EGFR. Western blot and immunohistochemistry results indicated that the over-activation of the AKT-STAT3 signaling pathway was inhibited. EHMF effectively reduced UV-induced skin damage, inflammation, and wrinkles, providing strong support for its clinical application as a dermatological agent.

Reflectance confocal microscopy for plaque psoriasis therapeutic follow-up during an anti-interleukin-17A monoclonal antibody: an observational study

Interleukin-17A therapeutic inhibitors are among the most effective treatment methods for moderate-to-severe plaque psoriasis (PP). Reflectance confocal microscopy is a non-invasive imaging technique already documented to be beneficial in evaluating the follow-up of PP under treatment with topical actives and phototherapy. This study aimed to assess the epidermal and dermal changes associated with psoriasis and its treatment with RCM during systemic secukinumab treatment in patients with moderate-to-severe PP. A pilot study was conducted to evaluate RCM as a non-invasive tool for monitoring secukinumab treatment in patients with PP. For patients receiving secukinumab treatment, lesional skin was selected for RCM imaging, which were recorded at all scheduled times. The RCM evaluation criteria were established based on the histopathological diagnostic criteria for psoriasis. The clinical severity of psoriasis was assessed utilizing the psoriasis area severity index. A total of 23 patients with PP were included in the study. Each patient received 300 mg of subcutaneous secukinumab as induction therapy at baseline and weeks 1–4, followed by maintenance therapy every four weeks. Microscopic confocal changes were observed during the treatment. The results identified early microscopic evidence of the anti-inflammatory activity of secukinumab, which was not detected during the clinical examination. RCM findings correlating with the PASI were used to observe the patient’s response to treatment and were identified as follows: acanthosis and parakeratosis, presence of epidermal and dermal inflammatory cells, presence of non-edge dermal papillae, and vascularization in the papillary dermis. This study is the first to demonstrate the use of RCM as an effective tool for non-invasive monitoring of secukinumab therapeutic response at a cellular level in a clinical or research setting. Early detection of RCM parameters associated with secukinumab activity may facilitate the identification of an early treatment response. RCM appears to be capable of providing practical and helpful information regarding follow-up in patients with PP undergoing secukinumab treatment. RCM may also provide novel perspectives on the subclinical evaluation of PP’s response to biological therapy.

Lapatinib prevents and ameliorates dermal fibrosis in bleomycin induced experimental scleroderma model

Background: Scleroderma is a connective tissue disease characterized by endothelial damage and diffuse interstitial fibrosis. Lapatinib, a tyrosine kinase inhibitor, is a 4-anilinoquinol derivative. It inhibits many important signalling pathways including MAPK and PI3K. As a result, it affects cell cycle progression, apoptosis, angiogenesis and cell adhesion. Materials and Methods: Mice with an average age of 6 weeks and a weight of 20-25 g were divided into 6 equal groups (n=10 in each group). Mice in the control group (group A and group D), which were not treated with bleomycin (BLM), received sc phosphate buffered saline (PBS) daily. BLM was dissolved in FTS and administered to mice in groups B and C for 3 weeks, and to mice in groups E and F at a dose of sc 100 L (100 g) daily for 6 weeks. Mice in groups A, B and C were sacrificed at the end of week 3; mice in groups D, E and F were sacrificed at the end of week 6 and tissue samples were collected for further analysis. The mRNA expressions of TGF-β1 and fibronectin-1 were determined by RT-PCR. Results: Repeated subcutaneous administration of BLM caused dermal inflammatory cell infiltration, increased skin thickness and dermal fibrosis at early and late stages. TGF-β1 and fibronectin-1 mRNA expressions were also evidently increased. In both prophylactic and therapeutic applications of lapatinib, TGF-β1 and fibronectin-1mRNA expressions decreased markedly. In addition, histopathological dermal necro- inflammation and fibrosis were reduced. Conclusions: Lapatinib may exert anti-fibrotic effects in BLM-induced dermal fibrosis model. Studies show that lapatinib is a potential therapeutic agent, but it needs to be confirmed with in vivo studies.

Immunohistochemical Demonstration of Mast Cells in Bovine Papillomatous Digital Dermatitis of Holstein-Friesian Dairy Cattle

Mast cells (MC)are unique members of immune system; their location and functions are of great importance in health and disease status. This study aims to evaluate MCs distribution and heterogenity in healthy and digital dermatitis lesions of dairy cattle for the first time. A total of 50 skin samples, 25 healthy and 25 with digital dermatitis (DD) lesions were sampled in Holstein-Friesian dairy cattle. All samples were stained with hematoxylin-eosin (H&E) for microscopic examination and also stained with Toluidine blue for MCs demonstration. Epidermal acanthosis and hyperkeratosis with dermal inflammatory cell infiltrations were in consistent with digital dermatitis lesions. Spirochetal agents were successfully demonstrated with Warthin-Starry staining in 22 out of 25 DD samples. Increased number of mast cell were observed in digital dermatitis samples when compared with healthy skin samples. The average number of intact MCs were 4.6 ± 2 and 9.3 ± 1 in healthy and digital dermatitis samples, respectively. Two-fold increase in the number of intact MCs in digital dermatitis samples was observed. Degranulated mast cell numbers in tissue sections were also higher in digital dermatitis samples and 4.25-fold increase was recorded in affected skin samples. Immunophenotype of MCs in skin samples were identified by immmunohistochemical stainings with anti-tryptase and chymase antibodies. Only tryptase positive MCs were observed in healthy and DD samples. In the statistical analysis, differences in the mean intact and degranulated MCs were found to be significant (mean intact: p<0.05, mean degranulated: p<0.01). Our results possibly suggest that MCs may have important roles in the pathogenesis of bovine digital dermatitis.

Understanding the anatomy of dermoscopy of melanocytic skin tumours: Correlation invivo with line-field optical coherence tomography.

Early melanoma detection is the main factor affecting prognosis and survival. For that reason, non-invasive technologies have been developed to provide a more accurate diagnosis. Recently, line-field confocal optical coherence tomography (LC-OCT) was developed to provide an invivo, imaging device, with deep penetration and cellular resolution in three dimensions. Combining the advantages of conventional OCT and reflectance confocal microscopy, this tool seems to be particularly suitable for melanocytic lesions. The objective of this study was to identify and describe the correlation between specific dermoscopic criteria and LC-OCT features in three dimensions associated with melanocytic lesions. Dermoscopic and LC-OCT images of 126 melanocytic lesions were acquired in three different centres. The following dermoscopic criteria have been considered: reticular pattern, dots and globules, structureless areas, blue-whitish veil, regression structures, negative network, homogeneous pattern, streaks and blotches. 69 (55%) benign and 57 (45%) malignant lesions were analysed. A regular reticular pattern was found associated in the 75% of the cases with the presence of elongated rete ridges with pigmented cells along the basal layer, while atypical reticular pattern showed an irregular organization of rete ridges with melanocytic hyperplasia, broadened and fused ridges and elongated nests. Both typical and atypical dots and globules were found associated with melanocytic nests in the dermis or at the dermoepidermal junction (DEJ), as well as with keratin cysts/pseudocysts. Grey globules corresponded to the presence of melanin-containing dermal inflammatory cells (melanophages) within the papillae. Structureless brown/black areas correlated with alterations of the DEJ. We observed the same DEJ alterations, but with the presence of dermal melanophages, in 36% of the cases of blue/white/grey structureless areas. A description of each LC-OCT/dermoscopy correlation was made. LC-OCT permitted for the first time to perform an invivo, 3D correlation between dermoscopic criteria and pathological-like features of melanocytic lesions.

Histological Evaluation of Arthritis in Mice

Arthritis is one the almost commonly prevalent painful diseases which cause limit the movement of joints. This study conducts to investigate histological alterations resulted in rheumatoid arthritis (RA)-induced in mice and estimating the levels of some serum biomarkers including serum IL-6, CRP and RF. Totally, 30 were purchased, acclimated, and divided into two groups; control that injected distilled water, and arthritis that injected adjuvant (CFA). Post the 25th day of experiment, all study mice of both groups were subjected for collection of blood and right ankle joints. Serologically, the findings of IL-6, CRP and RF of arthritis group were elevated significantly when compare to control mice. Histologically, the findings observed in mice of control group were included the proliferation of chondrocytes of articular cartilage with moderate cellular and subchondral marrow space, infiltration few inflammatory cells in dermis, proliferation of chondrocytes in articular cartilage with absence of inflammatory reaction in synovial cavity, moderate infiltration of inflammatory cells in subcutaneous tissue, nearly normal articular cartilage with regular tidemark and absence of sclerosis in marrow spaces, regenerative articular cartilage and regular tidemark line with presence of very narrow distance between articular cartilage and marrow bone, and existence of normal bone trabeculae. In arthritis mice, there were an infiltration of inflammatory cells in subcutaneous tissues and dermis, marked increases in numbers of osteoclasts, sclerosis, regular tidemark and proliferation of chondrocytes, low amonunt of abscesses in subcutaneous tissue, thickness of bone trabeculae, fragments of bone, subchondral sclerosis, moderate distance between bone and articular cartilage. In conclussion, RA causes severe impacts on tissues of affected joints. Studying the mechanism of inhibition during different inflammatory process appear needed.

Clinical and histopathological characteristics, diagnosis and treatment, and comorbidities of Bowen's disease: a retrospective study.

Bowen's disease (BD) is a slow-growing precancerous skin condition, often concurrent with other diseases, with a high misdiagnosis rate. Previous studies show that patients with BD in different populations have differentiated characteristics. A retrospective study was conducted in a tertiary hospital in Shenzhen, China. Data about demographic information, diagnosis and treatment, clinical and pathological characteristics, and comorbidities of 50 patients with BD were collected and analyzed. Clinical data of onset age and disease course of 43 patients with BD were available, the average onset age of male and female patients are 55.1 (standard deviation (SD) = 15.29) and 58.2 (SD = 15.59) years old, respectively; the average disease course of male and female patients are 25.3 (SD = 28.63) and 33.9 (SD = 49.65) months, respectively. The onset age (p = 0.52) and disease course (p = 0.49) between male and female patients are not significantly different. Interestingly, there is a negative correlation between onset age and disease course (r = -0.245, p = 0.11). The correct rate of clinical diagnosis is relatively low (54.00%); Some patients with BD are misdiagnosed as Bowenoid papulosis (10.00%), actinic keratosis (8.00%), basal cell carcinoma (8.00%), seborrheic keratosis (6.00%), and pigmented naevus (4.00%). Trunk and limbs are the most common distribution sites of BD lesions, and 94.00% patients with BD are treated with surgical resection; 66.00% patients with BD had comorbidities, including skin diseases (48.48%), cardiovascular diseases (39.39%), gastrointestinal diseases (30.30%), respiratory diseases (27.27%), and tumors (18.18%). The most commonly observed histopathological characteristics of BD are squamous-cell hyperplasia (86.00%), disordered maturation with atypical keratinocytes (74.00%), atypical mitoses (60.00%), hyperkeratosis with hypokeratosis (48.00%), dermal inflammatory cell infiltration (36.00%), and koilocytosis (22.00%). BD often occurs in middle-aged and elderly people and is easily misdiagnosed. The onset age and disease course of patients with BD are not significantly different between males and females, whereas there is a negative correlation between the onset age and disease course. BD is more likely to occur in trunk and limbs in the Chinese population, and most patients with BD are concurrent with comorbidities.

Study the involvement of Langerin in mediating epicutaneous sensitization of atopic dermatitis-like mouse model

Objective: To explore the role of Langerin in mediating epicutaneous sensitization of atopic dermatitis (AD) in mouse model. Methods: Mice were topically treated with calcipotriol (MC903) plus ovalbumin (OVA) on the ears to establish AD mouse models, and mice were divided into wild-type control group, wild-type AD group, Langerin knockout control group, and Langerin knockout AD group. Changes of lesion were daily observed. Infiltration of inflammatory cells, mRNA expression of Tslp, Il4, Il13, Il17a, and Il22, levels of serum total IgE, OVA-specific IgE (sIgE), OVA sIgG1 and OVA sIgG2a, proportion of regulatory T (Treg) cells in cervical draining lymph nodes were evaluated at the end of model preparation. Results: Skin tumidness and thickness, dermal inflammatory cells infiltration, the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 in wild-type AD groups were higher than those in wild-type control groups, with (1.80±0.66, 1.64±0.25, 1.71±0.54, 2.41±0.23, 2.49±0.32) and (0.53±0.45, 0.85±0.29, 0.73±0.50, 0.72±0.25, 0.56±0.29), respectively (all P<0.05). In addition, the levels of serum total IgE, OVA sIgE and OVA sIgG1 in wild-type AD groups were higher than those in wild-type control groups, with [(1 216.00±572.70) ng/ml, (597.00±538.30) ng/ml, 1.59±0.09] and [(24.22±35.04) ng/ml, (20.01±41.71) ng/ml, 1.16±0.03], respectively (all P<0.05). In Langerin knockout mice, compared to wild-type mice, skin erythema, skin tumidness, epidermal thickening, inflammatory cell infiltration were more obvious; the mRNA expression levels of Tslp, Il4, Il13, Il17a and Il22 were upregulated with (8.19±6.44, 2.53±0.69, 2.82±0.73, 3.94±1.32, 3.80±1.43) (all P<0.05); the levels of serum total IgE, OVA sIgE and OVA sIgG1 were significantly increased with (2 508.00±657.10) ng/ml, (1 808.00±470.70) ng/ml, (1.73±0.09) (all P<0.05); the number of CD4+CD25+CD127-Treg cells were decreased significantly with (13.25±0.96)% and (15.31±1.47)%, respectively (P<0.05). Conclusion: Langerin is involved in mediating epicutaneous sensitization of the AD mouse model and plays a negative immunoregulatory role.

Immunolocalization and Expression of JAK1 and JAK3 in the Skin of Dust Mite-Sensitive Beagle Dogs before and after Allergen Exposure.

Janus kinase (JAK) pathways have emerged as targets of treatment, yet localization and expression of JAK1 and JAK3 in canine atopic skin have not been studied. This study aimed to compare the localization and expression of JAK1 and JAK3 in the skin of atopic dogs before and after allergen exposure. Skin biopsies taken from atopic beagles sensitized to house dust mites (HDM) before (D0) and after four weeks (D28) of allergen exposure were stained. Staining was subjectively scored by examiners unaware of the source of the slides. Image J was used for the semiquantitative assessment of staining intensity. JAK1 and JAK3 staining was epidermal and dermal. JAK1 staining was cytoplasmic, primarily found in basal keratinocytes and dermal cells, while JAK 3 was nuclear (all epidermal levels and on dermal inflammatory cells). Epidermal thickness was significantly higher on D28 than on D0 (p < 0.0001). For JAK1, epidermal staining divided by epithelial thickness was significantly lower on D28 (p = 0.0002) compared to D0. For JAK3 staining, intensity in the dermis was significantly higher on D28 (p = 0.0405) compared to D0. We conclude that decreased expression of JAK1 in the epidermis and increased expression of JAK3 in the dermis of atopic dogs occur after allergen exposure.

Sodium thiosulfate ameliorates atopic dermatitis via inhibiting the activation of NLRP3 inflammasome

Atopic dermatitis (AD) is a common disease with a considerable impact on the patient's quality of life and limited treatment options. Sodium thiosulfate (STS) is a traditional medicine used in the rescue of cyanide poisoning, and some pruritus dermatosis. However, the exact efficacy and mechanism of its application on AD are not clear. In this work, comparing to other traditional therapy, STS was found to effectively improve the severity of skin lesions and the quality of life in AD patients with a dose-dependent manner. Mechanically, STS downregulated the expression of IL-4, IL-13, IgE in the serum of AD patients, as well as reduce the concentration of eosinophils. Furthermore, in the AD-like mice model triggered by ovalbumin (OVA) and calcitriol, STS was found to reduce the epidermal thickness, scratching times, and the infiltration of dermal inflammatory cells in AD mice, as well as the reactive oxygen species (ROS) production and the expression levels of inflammatory cytokines in the skin tissue. In HacaT cells, STS inhibited the accumulation of ROS and activation of NLRP3 inflammasome and its downstream IL-1β expression. Therefore, this study revealed that STS plays an important therapeutic role in AD, and the mechanism may be that STS inhibits the activation of NLRP3 inflammasome and the subsequent release of inflammatory cytokines. Thus, the role of STS in treating AD was clarified and the possible molecular mechanism was revealed.

Octyl Gallate, a Potential Therapeutic Candidate for Psoriasis: An In vitro and In silico Anti-Inflammatory approach

Background: Psoriasis is an inflammatory skin disease characterized by hyper-proliferating epidermal membrane and accumulation of dermal inflammatory cells. A profound understanding of mechanistic studies has revealed the potential role of TNF-α and IL-17a in disease pathogenesis. background: Psoriasis is an inflammatory skin disease labelled with hyper-proliferating epidermal membrane and accumulation of dermal inflammatory cells. Profound understanding of mechanistic studies revealed the potential role of TNF-α and IL-17a in the disease pathogenesis. Aim: The study aims to evaluate the inhibitory potential of octyl gallate on IL-17a through in silico analysis and validate its anti-inflammatory effects against oxidative stress and proinflammatory cytokines in vitro. Aim: The study aims to evaluate the inhibitory potential of octyl gallate on IL-17a through in silico analysis and validate its anti-inflammatory effects against oxidative stress and proinflammatory cytokines in vitro. Objective: The objective of the study is to evaluate the potential of octyl gallate for the treatment of psoriasis by targeting inflammatory mediators using in vitro and in silico approaches. Materials and Methods: The anti-oxidant potential of octyl gallate was evaluated through chemiluminescence and the Griess method. Cytotoxicity was evaluated via MTT assay. TNF-α levels were quantified through ELISA. Mechanistic studies were performed to recognize the inhibition of strong inflammatory mediators, such as TNF-α, IL-1β, IL-6, NCF-1, and NF-κB through gene expression analysis. Molecular docking was performed to study the underlying binding pattern of gallate inhibitor with IL-17a. result: Octyl gallate potently inhibited the TNF-α, reactive oxygen and nitrogen species while significantly reduces the expression of inflammatory genes. The docking analysis revealed that octyl gallate resides well in the binding pocket of IL17a. The physiochemical properties of gallate resulted good ADME profile. Results: Octyl gallate potently inhibited TNF-α, reactive oxygen, and nitrogen species while significantly reducing the expression of inflammatory genes. The docking analysis revealed that octyl gallate resides well in the binding pocket of IL17a. The physicochemical properties of gallate resulted in a good ADME profile. conclusion: Octyl gallate revealed significant antioxidant potential and downregulation of inflammatory genes principally involved in psoriasis. A new inhibitory target IL-17a of octyl gallate has been identified that together with TNF-α develops a feed forward state in disease pathogenesis. This study signifies the potential of octyl gallate to be a prospective lead molecule for treatment of psoriasis. Conclusion: Octyl gallate revealed a significant antioxidant potential and downregulation of inflammatory genes principally involved in psoriasis. A new inhibitory target IL-17a of octyl gallate has been identified that, together with TNF-α, develops a feed-forward state in disease pathogenesis. This study signifies the potential of octyl gallate to be a prospective lead molecule for the treatment of psoriasis. other: NA

Auranofin ameliorates psoriasis-like dermatitis in an imiquimod-induced mouse by inhibiting of inflammation and upregulating FA2H expression

Psoriasis vulgaris (PV) is a common inflammatory skin disorder with immune imbalance contributing to its pathology. It has been reported that auranofin, a known anti-rheumatic drug, has the therapeutic effects on inflammatory diseases. However, the effects and underlying mechanisms of auranofin on PV have not been reported. Here, we showed that auranofin significantly attenuated the mixture of five proinflammatory cytokines (termed as M5) induced hyperproliferation and inflammation in HaCaT cells, a kind of human immortalized keratinocyte cell line. Topical administration of auranofin markedly alleviated the imiquimod (IMQ)-induced mouse psoriatic dermatitis both in appearance and in pathology. The psoriasis area and severity index (PASI) score, acanthosis, dermal infiltrated inflammatory cells and Ki-67 expression were improved obviously. The results of RNA-sequencing from both M5-induced HaCaT cells and IMQ-treated mouse dermatitis showed that auranofin could regulate inflammation-related signaling pathway. Meanwhile, we observed that fatty acid 2-hydroxylase (FA2H), a key molecule in lipid metabolism, was significantly increased after auraonfin treatment in both M5-induced HaCaT cells and IMQ-treated mouse skin. Knockdown of FA2H in HaCaT cells remarkably inhibited cell apoptosis, increased cell proliferation and the expression profiles of inflammatory-related genes, whereas FA2H overexpression had opposite effect. In conclusion, auranofin notably alleviated IMQ-induced psoriasis-like skin inflammation, which might be mediated by increasing FA2H expression, suggesting its potential to be a novel strategy for psoriasis treatment.

Dietary supplementation of n-3 PUFAs ameliorates LL37-induced rosacea-like skin inflammation via inhibition of TLR2/MyD88/NF-κB pathway

Rosacea is a facial chronic inflammatory skin disease with dysfunction of immune and neurovascular system and treatments for rosacea are challenging. N-3 polyunsaturated fatty acids (PUFAs), one of essential fatty acids, are needed for health maintenance and exert anti-inflammation and immunomodulatory effects in a series of cutaneous diseases such as atopic dermatitis and photoaging through dietary supplementation. However, the role of n-3 PUFAs on rosacea remains to be elucidated. In this study, KEGG enrichment analysis and GO analysis indicated that the biological process and signaling pathways, including chemokine signaling pathway, regulated by n-3 PUFAs highly overlapped with those in the pathogenic biological process of rosacea, especially the erythema telangiectasia type. Next, mice were randomized to fed with a customized n-3 PUFAs diet. We showed that n-3 PUFAs ameliorated skin erythema, inhibited dermal inflammatory cell infiltration (mast cells, neutrophils, and CD4 +T cells) and suppressed elevated pro-inflammatory cytokines in LL37-induced rosacea-like mice. Besides, n-3 PUFAs were also verified to repress angiogenesis in LL37-induced mice skin. Further investigation revealed that n-3 PUFAs attenuated LL37-induced inflammation via TLR2/ MyD88/ NF-κB pathway both in mice and in keratinocytes. In conclusion, our findings underscore that dietary supplementation of n-3 PUFAs have the potential to become an efficient and safe clinical therapeutic candidate for rosacea.

Association of endothelial to mesenchymal transition and cellular senescence with fibrosis in skin biopsies of systemic sclerosis patients: a cross-sectional study.

Fibrosis is the dominant hallmark of systemic sclerosis (SSc). Several mechanisms have been proposed to drive the disease process, but how these relate to skin fibrosis is poorly understood. We performed a cross-sectional study on archival skin biopsies from 18 SSc patients and four controls. Dermal fibrosis and inflammatory cell infiltration were scored in HE and Masson's Trichrome-stained sections. The presence of senescence was defined by P21 and/or P16 positivity in Ki-67 negative cells. Endothelial to mesenchymal transition (EndMT) was identified by co-localisation of CD31 and α-SMA in immunofluorescent double-stained sections, and by an enclosure of ERG positive endothelial cell nuclei by α-SMA stained cytoplasm in immunohistochemical double staining. The histological dermal fibrosis score of SSc skin biopsies was correlated with the modified Rodnan skin score (rho 0.55, p=0.042). Staining for markers of cellular senescence on fibroblasts was correlated with fibrosis score, inflammatory score, and CCN2 staining on fibroblasts. Moreover, EndMT was more abundant in skin from patients with SSc (p<0.01) but did not differ between groups with different fibrosis severity. The frequency of these EndMT features increased with the abundance of senescence markers and CCN2 on fibroblasts and dermal inflammation. EndMT and fibroblast senescence were more abundant in skin biopsies from SSc patients. This finding indicates that both senescence and EndMT are involved in the pathway leading to skin fibrosis and might be valuable biomarkers and/or possible targets for novel therapeutic interventions.

Activation of aryl hydrocarbon receptor ameliorates rosacea-like eruptions in mice and suppresses the TLR signaling pathway in LL-37-induced HaCaT cells

BackgroundToll-like receptor (TLR) 2, along with some chemokines, were found to be overexpressed in rosacea patients. Aryl hydrocarbon Receptor (AhR) activation inhibited the inflammatory responses triggered by TLR activation. The current study was conducted to evaluate the underlying mechanisms of AhR activation in rosacea models. Materials and methodsSeven-week-old female BALB/c mice received twice daily intradermal injections of LL-37 for 2 consecutive days. Thirty minutes after the second LL-37 injection, 1% or 0.5% AhR agonist benvitimod was administrated topically once per day for 3 consecutive days. HaCaT cells were treated with different concentrations of LL-37 and benvitimod, and were further infected with lentivirus to over-express TLR2. Expressions of TLR2, CCL5, CXCL9, CXCL10 and CXCL11 were evaluated using qRT-PCR, Western Blot or ELISA. ResultsAhR activation ameliorated LL-37-induced rosacea-like eruptions in mice by reductions in redness scores, redness areas and dermal inflammatory cell infiltrates. Elevated expressions of TLR2 and chemokines (CCL5, CXCL9, CXCL10 and CXCL11) following LL-37 treatment were decreased by AhR activation. In HaCaT cells receiving LL-37, TLR2 and the four chemokines were up-regulated, and levels of these chemokines were further enhanced after over-expressing TLR2. At 8 h after an administration of 10 μM benvitimod, gene expressions of TLR2 and the four chemokines in LL-37 treated HaCat cells were decreased, while their protein expressions were decreased for 24 h. ConclusionAhR activation is beneficial in treating rosacea in a LL-37-induced rosacea mouse model and involves a suppression of the TLR signaling pathway in an HaCaT cell model of rosacea.

Notch1/Hes1‑PTEN/AKT/IL‑17A feedback loop regulates Th17 cell differentiation in mouse psoriasis‑like skin inflammation.

IL-17A, the effector cytokine of T helper (Th) 17 cells, plays a crucial role in the pathogenesis of psoriasis. The Notch1 and PI3K/AKT signaling pathways are implicated in Th17 cell differentiation and IL-17A production. The present study aimed to evaluate the regulatory effect of the Notch1/hairy and enhancer of split 1 (Hes1)-PTEN/AKT/IL-17A feedback loop on Th17 cell differentiation via the PI3K/AKT inhibitor LY294002 in a mouse model of psoriasis. Mice were randomly divided into 3 groups: a control group, a model group [5% imiquimod (IMQ)-induced group] and an intervention group (5% IMQ-induced plus LY294002-treated group). Skin structural characteristics were recorded and evaluated by hematoxylin and eosin staining. The weights of the spleens and inguinal lymph nodes were measured. Th17 cell percentage, as well as the mRNA and protein expression levels of Notch1, Notch1 intracellular domain (NICD1), Hes1, PTEN, AKT, phosphorylated (p)-AKT, mTOR complex 1 (mTORC1), p-mTORC1, S6 kinase (S6K)1, S6K2 and IL-17A were detected in skin samples of the three experimental groups. Additionally, splenic mononuclear cells from model mice were treated by 10 and 50 µM LY294002 to further evaluate its regulatory effect on Notch1/Hes1-PTEN/AKT/IL-17A feedback loop. Increased Th17 cell percentage, increased expression of Notch1, NICD1, Hes1, AKT, p-AKT, mTORC1, p-mTORC1, S6K1, S6K2 and IL-17A, and decreased PTEN levels were observed in model mice alongside marked psoriasis-like skin inflammation, splenomegaly and lymphadenopathy. LY294002 treatment significantly alleviated the severity of psoriasis-like skin inflammation in the intervention mice, attenuated the degree of epidermal hyperplasia and dermal inflammatory cell infiltration, and mitigated splenomegaly and lymphadenopathy. In addition, LY294002 treatment reversed the increased Th17 cell percentage, as well as the increased expression of Notch1, NICD1, Hes1, AKT, p-AKT, mTORC1, p-mTORC1, S6K1, S6K2 and IL-17A, and the decreased expression of PTEN. In vitro study from 5% IMQ-induced mouse splenic mononuclear cells presented that high dose of LY294002 exerted more obviously regulatory effect on Notch1/Hes1-PTEN/AKT/IL-17A feedback loop. The current findings suggested that the Notch1/Hes1-PTEN/AKT/IL-17A feedback loop regulates Th17 cell differentiation within the disease environment of psoriasis. Blocking the Notch1/Hes1-PTEN/AKT/IL-17A feedback loop may thus be a potential therapeutic method for management of psoriatic inflammation.

Sulforaphane Ameliorates the Severity of Psoriasis and SLE by Modulating Effector Cells and Reducing Oxidative Stress.

Background: Sulforaphane, which is found in cruciferous vegetables, has been reported to have anti-inflammatory, antioxidant, and antitumour activities. However, whether sulforaphane has therapeutic effects on inflammatory or autoimmune skin diseases, including psoriasis and systemic lupus erythematosus (SLE), is unclear. Methods: The therapeutic effects of sulforaphane were analyzed in Imiquimod (IMQ)-induced psoriasis-like mice and lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice treated with sulforaphane (55.3 and 110.6 μmol/kg) or vehicle control, the pathological phenotypes were assessed by the psoriasis area and severity index (PASI) score, haematoxylin-eosin staining (H&E) and quantifying of acanthosis and dermal inflammatory cell infiltration. The proportions of T cell subsets in draining lymph nodes (dLNs) and spleens were examined by flow cytometry. In MRL/lpr mice treated with sulforaphane (82.9 μmol/kg) or vehicle control, mortality and proteinuria were observed, and the glomerular pathology was examined by H&E staining. C3 and IgG depositions in kidney sections were examined by immunofluorescence staining. The proportions of plasma cells, follicular helper T (Tfh) cells, neutrophils and dendritic cells in the dLNs and spleens were examined by flow cytometry. Finally, we examined the Malondialdehyde (MDA) concentration by thiobarbituric acid reactive substance assay and the expression of Prdx1, Nqo1, Hmox1, and Gss by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: Sulforaphane ameliorated the skin lesions in IMQ-induced psoriasis-like mice and the renal damage in lupus-prone MRL/lpr mice. In IMQ-induced psoriasis-like mice, sulforaphane reduced the proportions of Th1 and Th17 cells and increased the expression of antioxidant gene Prdx1. In lupus-prone MRL/lpr mice, sulforaphane increased the lifespan and the expression of Prdx1, and decreased the proportions of plasma cells, Tfh cells, neutrophils, and dendritic cells in the dLNs and spleens and the concentration of MDA. Conclusion: Sulforaphane has significant therapeutic effects on IMQ-induced psoriasis-like mice and lupus-like MRL/Lpr mice by reducing inflammatory and autoimmune-related cells and oxidative stress. These findings provide new evidence for developing natural products to treat inflammatory and autoimmune diseases.

Effects of different concentrations of human umbilical cord mesenchymal stem cells to ameliorate psoriasis-like skin lesions in BALB/c mice.

BackgroundPsoriasis is an immune-mediated chronic, recurrent, inflammatory skin disease. In view of the research on the relationship between stem cells and the pathogenesis of psoriasis, stem cells may be a new breakthrough in the systemic treatment of psoriasis.MethodsThe BALB/c mouse psoriasis-like model induced by imiquimod was established and animals were randomly divided into a control group, model group, human umbilical cord mesenchymal stem cells (hUC-MSCs) group with different concentrations (injected separately with umbilical cord stem cells 1×107/kg, 2×107/kg, 4×107/kg through the caudal vein) and fresh hUC-MSCs group (injected with fresh umbilical cord stem cells 2×107/kg through the tail vein). The Psoriasis Area and Severity Index (PASI) score was used to observe the changes in skin lesions. The epidermal thickness, degree of keratinization and infiltration of inflammatory cells were observed by HE staining. The concentrations of TNF-α, IFN-γ, IL-17A, IL-23 and other cytokines in serum and skin of mice were measured by enzyme-linked immunosorbent assay (ELISA).ResultsMice treated with hUC-MSCs showed a good dose-response dependence compared with the control group. As the concentration of hUC-MSCs increased, so did the spleen index. According to the PASI integral trend chart, hUC-MSCs can delay the appearance of skin lesions and accelerate the recovery of skin lesions. HE staining showed that the number of parakeratosis cells in the hUC-MSCs treatment group was significantly decreased, and the degree of dermal hyperplasia and inflammatory cell infiltration in erythrocyte extravasation was significantly lower than in the model group. The higher the concentration of hUC-MSCs, the lower the concentration of the four cytokines in serum and skin tissue.ConclusionshUC-MSCs had an obvious therapeutic effect on imiquimod-induced psoriasis in mice, and a high concentration of hUC-MSCs had the best therapeutic effect. This effect intensity is dose-dependent, and hUC-MSCs at high concentrations have better therapeutic effect.

Epidermal Hyperproliferation With Less Prominent Dermal Inflammation Is the Unique Histopathological Feature of the Refractory Lesions in Psoriasis Treated With Ustekinumab.

Although ustekinumab (UST) shows excellent efficacy in treating psoriasis, not all patients have a complete clearance rate. The purpose of this study was to investigate the histopathological characteristics of refractory psoriasis lesions in patients with excellent response to UST. Fifty-seven patients with newly diagnosed psoriasis and 66 patients with a 75% reduction in the Psoriasis Area and Severity Index score after UST treatment were included. Computer-aided image analysis was performed to measure the epidermal thickness, horny layer thickness, number of dermal vessels, and dermal inflammatory cell infiltration rate. Parakeratosis was scored using a 4-point scale. These measurements were compared between the refractory lesions of UST-treated patients and the untreated lesions of newly diagnosed patients after the adjustment for confounding factors. The dermal inflammatory cell infiltration rate was significantly lower in the refractory lesions (P = 0.022). Meanwhile, the epidermal thickness, horny layer thickness, grade of parakeratosis, and dermal vessel count did not differ between the groups (P = 0.125, 0.719, 0.542, and 0.758, respectively). Subgroup analyses were performed within the UST-treated group after dividing them into 2 groups according to the number of treatments or treatment response rates. None of these features were significantly different between the subgroups. This study suggests that the reduction of dermal inflammation by UST was not sufficient to ameliorate the epidermal changes and implies the role of the interleukin-23-independent downstream cytokine pathway in causing the refractory lesions among patients who responded well to UST. The continuation of UST treatment might not further improve epidermal alterations.