Inflammatory Responses In Skin Research Articles

A New Eucalyptol-Rich Lavender (Lavandula stoechas L.) Essential Oil: Emerging Potential for Therapy against Inflammation and Cancer.

Background/Aim: natural products are a potential source for drug discovery and development of cancer chemoprevention. Considering that drugs currently available for the treatment of inflammatory and cancer conditions show undesirable side effects, this research was designed to evaluate, for the first time, the in vitro anticancer activity of Algerian Lavandula stoechas essential oil (LSEO) against different cancer cell lines, as well as its in vitro and in vivo topical and acute anti-inflammatory properties. Materials and Methods: the LSEO was extracted by steam distillation, and chemical composition analysis was performed using gas chromatography. The main compounds identified in LSEO were oxygenated monoterpenes, such as 1,8-Cineole (61.36%). LSEO exhibited a potent anti-inflammatory activity using the xylene-induced mouse ear edema model. Results: LSEO (200 and 20 mg/kg) was able to significantly reduce (p < 0.05) the carrageenan-induced paw edema with a similar effect to that observed for the positive control. Topical application of LSEO at doses of 82 and 410 mg/kg significantly reduced acute ear edema in 51.4% and 80.1% of the mice, respectively. Histological analysis confirmed that LSEO inhibited the skin inflammatory response. Moreover, LSEO was tested for its antitumor activity against different cancer cell lines. LSEO was found to be significantly active against human gastric adenocarcinoma (AGS), Melanoma MV3, and breast carcinoma MDA-MB-231 cells, with median inhibitory concentration (IC50) values of 0.035 ± 0.018, 0.06 ± 0.022 and 0.259 ± 0.089 µL/mL, respectively. Altogether, these results open a new field of investigation into the characterization of the molecules involved in anti-proliferative processes. Conclusion: We suggest that LSEO, with 1,8-Cineole as the major active component, is a promising candidate for use in skin care products with anti-inflammatory and anticancer properties. The results of this study may provide an experimental basis for further systematic research, rational development, and clinical utilization of lavender resources.

031 Enhancement of Th2 cell differentiation by TRIM32 deficiency is negatively associated with PKCζ

Atopic dermatitis (AD) is a chronic skin inflammatory disease characterized by skin barrier defects and the sustained activation of Th2-related inflammation. Despite the importance of Th2 activation in AD pathogenesis, the mechanism of Th2 activation in AD remains largely elusive. Tripartite motif-containing protein 32 (TRIM32) is an E3 ubiquitin ligase with innate antiviral activity. In our previous studies, we showed that Trim32 null mice developed Th2 biased skin inflammation in response to imiquimod and associated low level of TRIM32 with AD.

The Gastrointestinal Helminth Heligmosomoides bakeri Suppresses Inflammation in a Model of Contact Hypersensitivity.

Helminths regulate host immune responses to ensure their own long-term survival. Numerous studies have demonstrated that these helminth-induced regulatory mechanisms can also limit host inflammatory responses in several disease models. We used the Heligmosomoides bakeri (Hb) infection model (also known as H. polygyrus or H. polygyrus bakeri in the literature) to test whether such immune regulation affects skin inflammatory responses induced by the model contact sensitiser dibutyl phthalate fluorescein isothiocynate (DBP-FITC). Skin lysates from DBP-FITC-sensitized, Hb-infected mice produced less neutrophil specific chemokines and had significantly reduced levels of skin thickening and cellular inflammatory responses in tissue and draining lymph nodes (LNs) compared to uninfected mice. Hb-induced suppression did not appear to be mediated by regulatory T cells, nor was it due to impaired dendritic cell (DC) activity. Mice cleared of infection remained unresponsive to DBP-FITC sensitization indicating that suppression was not via the secretion of Hb-derived short-lived regulatory molecules, although long-term effects on cells cannot be ruled out. Importantly, similar helminth-induced suppression of inflammation was also seen in the draining LN after intradermal injection of the ubiquitous allergen house dust mite (HDM). These findings demonstrate that Hb infection attenuates skin inflammatory responses by suppressing chemokine production and recruitment of innate cells. These findings further contribute to the growing body of evidence that helminth infection can modulate inflammatory and allergic responses via a number of mechanisms with potential to be exploited in therapeutic and preventative strategies in the future.

Peppermint (Mentha piperita L.) essential oil as a potent anti-inflammatory, wound healing and anti-nociceptive drug

The present investigation was designed to study the chemical composition of Algerian peppermint essential oil (PEO) as well as the in vitro and in vivo anti-inflammatory, wound-healing and anti-nociceptive properties. Twenty-three compounds were identified in the PEO with the main chemical component as menthol (53.29%). Also, PEO showed a high content of oxygenated monoterpene compounds (92.75%). Topical application of PEO at doses of 200 and 20 µL/kg significantly reduced the acute ear edema in 38.09% and 36.50, respectively. Histological observation confirmed that PEO inhibited the skin inflammatory response. In-vivo wound healing activity of the cream prepared from PEO (0.5% w/w) was assessed by circular excision wound model followed by histological examination. The topical administration of PEO cream showed a significant decrease of unhealed wound area rate between the 6th (1.67±0.14 mm2) and the 9th (0.49±0.22 mm2) days of treatment when compared with the vehicle (2.32±0.77 mm2; p<0.05) and Madecassol® 0.1% creams (2.23±0.35 mm2; p<0.05). The PEO reduced nociceptive behavior at all doses tested in the acetic acid-induced nociception test (p<0.05). These findings support the anti-inflammatory, wound-healing and analgesic properties of PEO. We suggest that PEO is a promising candidate for use in skin care products with anti-inflammatory and wound-healing properties. DOI: http://dx.doi.org/10.5281/zenodo.3831042

Effects of dietary n-6:n-3 fatty acid ratio on growth performance, plasma fatty acid profile, intestinal morphology, and immune function of pigs

A total of 185 crossbred pigs (Yorkshire x Landrace; 20.7 ± 2.5 d of age and 6.7 ± 1.1 kg BW) from 3 weaning groups were used to evaluate dietary n-6:n-3 fatty acid (FA) ratios on nursery and growing pigs. Within each weaning group, pigs were blocked by BW and randomly assigned to 1 of 5 dietary treatments in a randomized complete block design with balanced sex and 4 or 5 pigs/pen within each block. The dietary treatments were: 1) low n-6:n-3 FA ratio (LO): 5.0% menhaden oil (MO) and 0.0% corn oil (CO); 2) low-medium n-6:n-3 FA ratio (LO-MED): 3.5% MO and 1.5% CO; 3) medium n-6:n-3 FA ratio (MED): 1.5% MO and 3.5% CO; 4) high-medium n-6:n-3 FA ratio (HI-MED): 0.2% MO and 4.8% CO; and 5) high n-6:n-3 FA ratio (HI): 0.0% MO and 5.0% CO. The diets were fed in 2 phases as d 0 to 28 (nursery phase) and d 29 to 70 (grower phase). In vivo cell-mediated immune response was assessed on d 14 and 28 for Group 1 and 2 by measuring the inflammatory response to an intradermal injection of 100 µL of phosphate buffered saline (PBS) or phytohemagglutinin (PHA, 0.5 mg/mL of PBS). One pig was euthanized from each pen in Group 1 and 2 at the end of the nursery and grower phase to assess intestinal morphology. During the nursery or grower phase, average daily gain (ADG), average daily feed intake (ADFI), and gain to feed ratio were not affected by increasing dietary n-6:n-3 FA ratios (P > 0.16). However, pigs fed the LO diet had lower (P < 0.05) ADG and ADFI compared to those fed diets containing greater n-6:n-3 FA ratios during the nursery phase. Increasing dietary n-6:n-3 FA ratio altered plasma n-6:n-3 FA ratios on d 15 and d 29 (quadratic, P < 0.01). In vivo cell-mediated immune response to PHA did not differ among treatments. Duodenum and jejunum villus height and villus height:crypt depth ratio did not differ among pigs on different treatments at the end of either the nursery or grower phase (P > 0.10). Jejunum crypt depth increase in a quadratic manner at the end of the nursery phase (P < 0.05) but not at the end of the grower phase (P > 0.10). In summary, increasing dietary n-6:n-3 FA ratios altered plasma n-3 FA concentration and n-6:n-3 FA ratio and might influence the intestinal morphology, but did not generally affect growth performance or the skin inflammatory response of pigs in the nursery or grower phases.

Interleukin (IL)-17/IL-36 axis participates to the crosstalk between endothelial cells and keratinocytes during inflammatory skin responses.

In inflammatory skin conditions, such as psoriasis, vascular enlargement is associated with endothelial cell proliferation, release of cytokines and adhesion molecule expression. Interleukin (IL)-17A is a pro-inflammatory cytokine mainly secreted by T helper-17 cells that is critically involved in psoriasis pathogenesis. IL-36α, IL-36β and IL-36γ are also inflammatory cytokines up-regulated in psoriasis and induced by various stimuli, including IL-17A. In this study, we found that human keratinocytes are the main source of IL-36, in particular of IL-36γ. This cytokine was strongly induced by IL-17A and, together with IL-17A, efficiently activated human dermal microvascular endothelial cells (HDMECs), which expressed both IL-17 and IL-36 receptors. Both IL-36γ and IL-17A induced cell proliferation through specific molecular cascades involving ERK1/2 only or ERK1/2, STAT3 and NF-κB, respectively. We highlighted the intense IL-17A- and IL-36γ -dependent interplay between keratinocytes and HDMECs, likely active in the psoriatic lesions and leading to the establishment of a cytokine network responsible for the development and maintenance of the inflamed state. IL-17A or IL-36γ showed in HDMECs a synergic activity with TNF-α by potently inducing inflammatory cytokine/chemokine release and ICAM-1 expression. We also investigated the involvement of IL-36γ and VEGF-A, substantially reduced in lesional skin of psoriatic patients pharmacologically treated with the anti-IL-17A antibody Secukinumab. Importantly, keratinocyte-derived IL-36γ represented an additional pro-angiogenic mediator of IL-17A. We observed that keratinocyte-derived VEGF-A influenced proliferation but did not act on expression of adhesion molecules in HDMECs. On the other hand, inhibition of IL-36γ released by IL-17A-treated keratinocytes impaired either proliferation or ICAM-1 expression both in HDMECs and in an in vivo murine model of psoriasis. Taken together, our data demonstrated that IL-17A and IL-36γ are highly involved in endothelial cells/keratinocytes crosstalk in inflammatory skin conditions.

Cutaneous wound healing in aged, high fat diet-induced obese female or male C57BL/6 mice.

Since there are limited studies analyzing the impact of age, sex and obesity on cutaneous repair, the current study evaluated excisional skin wound healing as a function of age, sex and diet in C57BL/6 mice subjected to either low (LFD) or high (HFD) fat diet. Older mice accumulated increased body fat relative to younger mice under HFD. Skin wound healing at particular stages was affected by age in the aspect of Tgfβ-1, MCP-1, Mmp-9 and Mmp-13 expression. The most profound, cumulative effect was observed for the combination of two parameters: age and sex. While skin of younger males displayed extremely high collagen 1 and collagen 3 expression, younger females showed exceptionally high Mmp-13 expression at day 3 and 7 after injury. Diet as a single variable modified the thickness of dermis due to increased dermal White Adipose Tissue (dWAT) accumulation in mice fed HFD. The combination of age and diet affected the re-epithelialization and inflammatory response of injured skin. Overall, our data indicate that age has the most fundamental impact although all components (age, sex and diet) contribute to skin repair.

A positive feedback loop between alpha1-adrenoceptors and inflammatory cytokines in keratinocytes

A positive feedback loop between inflammatory cytokines and alpha1-adrenoceptors (α1-AR) (a target of the sympathetic nervous system neurotransmitter norepinephrine) influences inflammatory responses in immune cells. This cross-talk between the sympathetic nervous system and immune system may play a role in promoting chronic inflammation. Emerging evidence shows that α1-AR interact with inflammatory cytokines in keratinocytes, and this epidermal adrenergic signalling may contribute to skin inflammatory responses following injury, disease or stress. In this study, utilizing an in vitro approach, we hypothesized that α1-AR interact in a positive feedback loop with inflammatory mediators in keratinocytes. The pro-inflammatory cytokine tumor necrosis factor α (TNFα) was used to induce an inflammatory state in cultured keratinocytes. TNFα increased interleukin (IL)-1β, IL-6, IL-8 and nerve growth factor (NGF) production and gene expression levels of α1-AR subtype B (α1B-AR). Additional stimulation of α1-AR further increased IL-6 levels, while maintaining high levels of IL-8 and decreasing levels of IL-1β and NGF. Our results suggest that reciprocal influences between α1-ARs and inflammatory cytokines may play a role in normal inflammatory responses. However, if unchecked, this cycle could contribute to pathology (e.g. chronic inflammatory diseases, chronic pain conditions, and stress-induced cancer progression).

Bucillamine Inhibits UVB-Induced MAPK Activation and Apoptosis in Human HaCaT Keratinocytes and SKH-1 Hairless Mouse Skin.

Ultraviolet B (UVB) radiation is known as a culprit in skin carcinogenesis. We have previously reported that bucillamine (N-[2-mercapto-2-methylpropionyl]-L-cysteine), a cysteine derivative with antioxidant and anti-inflammatory capacity, protects against UVB-induced p53 activation and inflammatory responses in mouse skin. Since MAPK signaling pathways regulate p53 expression and activation, here we determined bucillamine effect on UVB-mediated MAPK activation in vitro using human skin keratinocyte cell line HaCaT and in vivo using SKH-1 hairless mouse skin. A single low dose of UVB (30mJcm-2 ) resulted in increased JNK/MAPK phosphorylation and caspase-3 cleavage in HaCaT cells. However, JNK activation and casaspe-3 cleavage were inhibited by pretreatment of HaCaT cells with physiological doses of bucillamine (25 and 100µm). Consistent with these results, bucillamine pretreatment in mice (20mgkg-1 ) inhibited JNK/MAPK and ERK/MAPK activation in skin epidermal cells at 6-12 and 24h, respectively, after UVB exposure. Moreover, bucillamine attenuated UVB-induced Ki-67-positive cells and cleaved caspase-3-positive cells in mouse skin. These findings demonstrate that bucillamine inhibits UVB-induced MAPK signaling, cell proliferation and apoptosis. Together with our previous report, we provide evidence that bucillamine has a photoprotective effect against UV exposure.

Exosomes from Human Adipose Tissue-Derived Mesenchymal Stem Cells Promote Epidermal Barrier Repair by Inducing de Novo Synthesis of Ceramides in Atopic Dermatitis.

Atopic dermatitis (AD) is a multifactorial, heterogeneous disease associated with epidermal barrier disruption and intense systemic inflammation. Previously, we showed that exosomes derived from human adipose tissue-derived mesenchymal stem cells (ASC-exosomes) attenuate AD-like symptoms by reducing multiple inflammatory cytokine levels. Here, we investigated ASC-exosomes’ effects on skin barrier restoration by analyzing protein and lipid contents. We found that subcutaneous injection of ASC-exosomes in an oxazolone-induced dermatitis model remarkably reduced trans-epidermal water loss, while enhancing stratum corneum (SC) hydration and markedly decreasing the levels of inflammatory cytokines such as IL-4, IL-5, IL-13, TNF-α, IFN-γ, IL-17, and TSLP, all in a dose-dependent manner. Interestingly, ASC-exosomes induced the production of ceramides and dihydroceramides. Electron microscopic analysis revealed enhanced epidermal lamellar bodies and formation of lamellar layer at the interface of the SC and stratum granulosum with ASC-exosomes treatment. Deep RNA sequencing analysis of skin lesions demonstrated that ASC-exosomes restores the expression of genes involved in skin barrier, lipid metabolism, cell cycle, and inflammatory response in the diseased area. Collectively, our results suggest that ASC-exosomes effectively restore epidermal barrier functions in AD by facilitating the de novo synthesis of ceramides, resulting in a promising cell-free therapeutic option for treating AD.

Omiganan Enhances Imiquimod‐Induced Inflammatory Responses in Skin of Healthy Volunteers

Omiganan (OMN; a synthetic cationic peptide) and imiquimod (IMQ; a TLR7 agonist) have synergistic effects on interferon responses in vitro. The objective of this study was to translate this to a human model for proof‐of‐concept, and to explore the potential of OMN add‐on treatment for viral skin diseases. Sixteen healthy volunteers received topical IMQ, OMN, or a combination of both for up to 4 days on tape‐stripped skin. Skin inflammation was quantified by laser speckle contrast imaging and 2D photography, and molecular and cellular responses were analyzed in biopsies. IMQ treatment induced an inflammatory response of the skin. Co‐treatment with OMN enhanced this inflammatory response to IMQ, with increases in perfusion (+17.1%; 95% confidence interval (CI) 5.6%–30%; P < 0.01) and erythema (+1.5; 95% CI 0.25%–2.83; P = 0.02). Interferon regulatory factor‐driven and NFκB‐driven responses following TLR7 stimulation were enhanced by OMN (increases in IL‐6, IL‐10, MXA, and IFNɣ), and more immune cell infiltration was observed (in particular CD4+, CD8+, and CD14+ cells). These findings are in line with the earlier mechanistic in vitro data, and support evaluation of imiquimod/OMN combination therapy in human papillomavirus‐induced skin diseases.

Cannabinoid Receptor 2 Modulates Maturation of Dendritic Cells and Their Capacity to Induce Hapten-Induced Contact Hypersensitivity.

Contact hypersensitivity (CHS) is an established animal model for allergic contact dermatitis. Dendritic cells (DCs) play an important role in the sensitization phase of CHS by initiating T cell responses to topically applied haptens. The cannabinoid receptors 1 (CB1) and 2 (CB2) modulate DC functions and inflammatory skin responses, but their influence on the capacity of haptenized DCs to induce CHS is still unknown. We found lower CHS responses to 2,4-dinitro-1-fluorobenzene (DNFB) in wild type (WT) mice after adoptive transfer of haptenized Cnr2−/− and Cnr1−/−/Cnr2−/− bone marrow (BM) DCs as compared to transfer of WT DCs. In contrast, induction of CHS was not affected in WT recipients after transfer of Cnr1−/− DCs. In vitro stimulated Cnr2−/− DCs showed lower CCR7 and CXCR4 expression when compared to WT cells, while in vitro migration towards the chemokine ligands was not affected by CB2. Upregulation of MHC class II and co-stimulatory molecules was also reduced in Cnr2−/− DCs. This study demonstrates that CB2 modulates the maturation phenotype of DCs but not their chemotactic capacities in vitro. These findings and the fact that CHS responses mediated by Cnr2−/− DCs are reduced suggest that CB2 is a promising target for the treatment of inflammatory skin conditions.

Intrauterine growth restriction induces skin inflammation, increases TSLP and impairs epidermal barrier function.

Intrauterine growth restriction (IUGR) and low birth weight are risk factors for childhood asthma. Atopic march describes the progression from early dermatitis to asthma during life. Since inflammatory signaling is linked to increased airway resistance and lung remodeling in rats after IUGR, we queried if these findings are related to skin inflammatory response. Firstly, we induced IUGR in Wistar rats by isocaloric protein restriction during gestation. IUGR rats showed lower body weight at postnatal day 1 (P1), catch-up growth at P21, and similar body weight like controls at P90. At P1 and P90, mRNA of inflammatory as well as fibrotic markers and number of skin immune cells (macrophages) were increased after IUGR. Skin thymic stromal lymphopoietin (TSLP) mRNA at P1 and serum TSLP at P1 and P21 were elevated in IUGR. Moreover, IUGR impaired transepidermal water loss at P21 and P90. IUGR induced higher. Secondly, the increase of TEWL after Oxazolone treatment as a model of atopic dermatitis (AD) was greater in IUGR than in Co. Our data demonstrate an early inflammatory skin response, which is linked to persistent macrophage infiltration in the skin and impaired epidermal barrier function after IUGR. These findings coupled with elevated TSLP could underlie atopic diseases in rats after IUGR. KEY MESSAGES: • The present study shows that IUGR increases macrophage infiltration and induces an inflammatory and fibrotic gene expression pattern in the skin of newborn rats. • Early postnatal inflammatory response in the skin after IUGR is followed by impaired epidermal barrier function later in life. • IUGR aggravates transepidermal water loss in an experimental atopic dermatitis model, possibly through elevated TSLP in skin and serum. • Early anti-inflammatory treatment and targeting TSLP signaling could offer novel avenues for early prevention of atopic disorders and late asthma in high-risk infants.

Intercellular Arc Signaling Regulates Vasodilation

Injury responses require communication between different cell types in the skin. Sensory neurons contribute to inflammation and can secrete signaling molecules that affect non-neuronal cells. Despite the pervasive role of translational regulation in nociception, the contribution of activity-dependent protein synthesis to inflammation is not well understood. To address this problem, we examined the landscape of nascent translation in DRG neurons treated with inflammatory mediators using ribosome profiling. We identified the activity-dependent gene, Arc, as a target of privileged translation in vitro and in vivo. Inflammatory cues promote local translation of Arc in the skin. Arc deficient mice display exaggerated paw temperatures and vasodilation in response to an inflammatory challenge. Since Arc has recently been shown to be released from neurons in extracellular vesicles, we hypothesized that intercellular Arc signaling regulates the inflammatory response in skin. We found that the excessive thermal responses and vasodilation observed in Arc defective mice are rescued by injection of Arc-containing extracellular vesicles into the skin. Our findings suggest that activity-dependent production of Arc in afferent fibers regulates neurogenic inflammation through intercellular signaling.

Skin inflammatory response and efficacy of anti-epidermal growth factor receptor therapy in metastatic colorectal cancer (CUTACETUX)

ABSTRACT Anti-epidermal growth factor receptor (EGFR) monoclonal antibody is a standard treatment of metastatic colorectal cancer (mCRC) and its most common adverse effect is a papulopustular acneiform rash. The aim of the CUTACETUX study was to characterize the skin inflammatory response associated with this rash and its relation to treatment efficacy. This prospective study included patients with mCRC treated with first-line chemotherapy plus cetuximab. Patients underwent skin biopsies before the initiation of cetuximab (D0) and before the third infusion (D28), one in a rash zone and one in an unaffected zone. Expression of Th17-related cytokines (IL-17A, IL-21, IL-22), antimicrobial peptides (S100A7 and BD-2), innate response-related cytokines (IL-1β, IL-6, TNF-α and OSM), T-reg-related cytokines (IL-10 and TGF-β), Th1-related cytokine (IFN-γ), Th2-related cytokine (IL-4), Thymic stromal lymphopoietin and keratinocyte-derived cytokines (IL-8, IL-23 and CCL20) were determined by RT-PCR. Twenty-seven patients were included. Levels of most of the cytokines increased at D28 in the rash zone compared to D0. No significant association was observed between variations of cytokines levels and treatment response in the rash zone and only the increase of IL-4 (p = .04) and IL-23 (p = .02) levels between D0 and D28 in the unaffected zone was significantly associated with treatment response. Increased levels of IL-8 (p = .02), BD-2 (p = .02), IL-1β (p = .004) and OSM (p = .02) in the rash zone were associated with longer progression-free survival. Expression of Th2-related and keratinocyte-derived cytokines in the skin was associated with anti-EGFR efficacy. If this inflammatory signature can explain the rash, the exact mechanism by which these cytokines are involved in anti-EGFR tumor response remains to be studied.

High plasma dopamine level as a risk factor for atopic dermatitis

Background: Dopamine is responsible for inflammatory response and plays a role in the skin immune system by modulating T-cells, dendritic cells, and keratinocytes which increases skin inflammatory response in atopic dermatitis (AD). Elevation of dopamine level will affect IL-6, IL-8, IL-23, Th-17, and TNF-α, which promotes keratinocyte proliferation and differentiation, infiltration of inflammatory cells, angiogenesis, vasodilation, and skin barrier disruption on AD.Objective: This study aimed to establish whether the increase of plasma dopamine level contributes to a risk factor for AD occurrence.Methods: This is a matched-pair case-control observational analytical study which involves patients with AD and without AD as control. Samples were taken using a consecutive sampling method which fulfilled inclusion and exclusion criteria, matched for gender and age. Plasma dopamine level was measured from venous blood and processed using enzyme-linked immunosorbent assay (ELISA) method. The collected data were then analysed using SPSS version 20.0 with Pearson chi-square test for the odds ratio.Results: A total of 30 samples with AD (case group) and 30 samples without AD (control group) involved in this study. This study proves that plasma dopamine levels in the case group were significantly higher than the control group (p&lt;0.05). Odds ratio for plasma dopamine was 42.2 (95%CI: 9.5-187.2, p &lt; 0.001).Conclusion: This study concludes that high plasma dopamine level is a risk factor for AD.

SERPINB2 and miR-146a/b are coordinately regulated and act in the suppression of psoriasis-associated inflammatory responses in keratinocytes.

Psoriasis is a chronic inflammatory skin disease with numerous involved factors. miR-146a and miR-146b (miR-146a/b) are anti-inflammatory miRNAs that are increased in psoriatic skin. SERPINB2 has been shown to be upregulated in the inflammation and infections. Here we aimed to study the relationship between miR-146a/b and SERPINB2 and to delineate the role of SERPINB2 in association of plaque psoriasis. We report increased SERPINB2 expression in the skin of psoriasis patients, which was in a positive relationship with psoriasis severity and in a negative relationship with miR-146a/b in psoriatic lesions. In cultured keratinocytes, both cellular and secreted SERPINB2 levels were strongly induced in response to IFN-γ and TNF-α. Interestingly, SERPINB2 mRNA was downregulated by IL-17A and the combination of TNF-α and IL-17A at time points when miR-146a was increased. The predicted binding site for miR-146a/b in 3' untranslated region of SERPINB2 revealed no activity in luciferase assay, while siRNA silencing of miR-146a/b direct targets IRAK1 and CARD10 resulted in reduced expression of SERPINB2, suggesting that miR-146a/b indirectly control SERPINB2 expression in the skin. The siRNA silencing of SERPINB2 increased the expression of IL-8, CXCL5 and CCL5 and migration of neutrophils revealing its anti-inflammatory role in keratinocytes. Our data together suggest that SERPINB2 and miR-146a/b are part of disease-related network of molecules that are coordinately regulated and act in controlling the inflammatory responses in psoriatic skin.

The anthocyanin extracts from purple-fleshed sweet potato exhibited anti-photoaging effects on ultraviolent B-irradiated BALB/c-nu mouse skin

Abstract This study investigated the effect of anthocyanin extracts from purple-fleshed sweet potato (PSP-AE) on ultraviolet B (UVB)-induced skin photoaging in BALB/c-nu mice. UPLC-QTOF-MS analysis showed six compounds were identified from PSP-AE. Administration of PSP-AE ameliorated the UVB-irradiated macroscopic and histopathological lesions of the skin via suppressing epidermal hyperplasia and collagen degradation, while improving the content of skin moisture and hydroxyproline. Additionally, PSP-AE inhibited the UVB-induced oxidative stress and increased the antioxidant enzyme activities. Results showed PSP-AE inhibited the UVB-irradiated levels of pro-inflammatory cytokines, such as tumor necrosis factor α and interleukin 6. Furthermore, Western blot analysis revealed PSP-AE remarkably decreased the protein levels of phosphorylated c-Jun-Nterminal kinase, extracellular signal-regulated kinase, and p38. Likewise, UVB induced nuclear translocation of nuclear factor kappa-B and the expression of matrix metalloproteinase 1 were diminished by pretreatment of PSP-AE. Therefore, PSP-AE had the potential to attenuate the UVB-irradiated skin oxidative stress and inflammatory response.

Elimination of KLK5 inhibits early skin tumorigenesis by reducing epidermal proteolysis and reinforcing epidermal microstructure

Epidermal desquamation involves a finely-tuned proteolytic cascade ensuring the regulated cleavage of desmosomes that releases old stratum corneum outermost layers. Although the roles of desmosomes in normal physiology are well-established, their putative involvement in cancer remains unexplored. The KLK5 protease is thought of having fundamental roles in epidermal proteolysis and homeostasis, and its aberrant activity has been linked to skin pathologies. We found that deletion of Klk5 results in significantly higher numbers of lengthier desmosomes and enhanced skin strength. Klk5−/− mice retained normal skin barrier function and are resistant to chemically-induced skin tumorigenesis. The resistance to tumorigenesis was not due to inhibition of inflammation, and on the contrary, absence of Klk5 increased the TPA-induced inflammatory skin response. We found that increased desmosomes and reduced proteolysis prevent oncogenic signaling by capturing β-catenin into the cytoplasm and facilitate epidermal keratinocyte apoptosis, thus, inhibiting tumor initiation. We highlight that the skin ultrastructure affects early neoplastic transformation by modulating intracellular signaling and suggest that tissue reinforcement provides a novel mode of tumor suppression.

Acupuncture Needling, Electroacupuncture, and Fire Needling Improve Imiquimod-Induced Psoriasis-Like Skin Lesions through Reducing Local Inflammatory Responses

Psoriasis is a common autoimmune disease. Acupuncture-related techniques have been widely used to treat psoriasis since its ability to engage neuronal function, the immune system, and other systems is well documented. This study aimed to investigate and compare the effects of three common acupuncture-related techniques in psoriasis-like skin inflammatory responses and explore the possible involved mechanisms. Imiquimod (IMQ)-induced psoriasis-like mice were treated with acupuncture needling, electroacupuncture, or fire acupuncture. Methotrexate (MTX) was applied as a positive control. Scoring by the psoriasis area and severity index (PASI) evaluated skin lesion changes. Keratinocyte proliferation and inflammatory cell infiltration were investigated using pathological staining. The secretion levels of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The expression levels of neuropeptides were assessed by Western immunoblotting. We found that acupuncture needling, electroacupuncture, and fire acupuncture all ameliorated skin lesions, reduced epidermal thickness, inhibited keratinocyte proliferation, and reduced CD3+ T cell infiltration. The aforementioned acupuncture techniques also decreased inflammatory cytokine secretion, including IL-1β, IL-17A, and IL-23p40. Among them, electroacupuncture showed the best curative effects. Additionally, electroacupuncture downregulated the expression levels of Neurokinin A (NKA), which was positively associated with decreased inflammatory cytokine levels in local lesions. In conclusion, acupuncture needling, electroacupuncture, and fire acupuncture alleviated IMQ-induced psoriasis-like lesions. By contrast, electroacupuncture was more beneficial in reducing the inflammatory response, which might be related to locally dampened neuropeptide levels. Observations support the therapeutic effect of acupuncture for psoriasis and indicate a neuromodulatory mechanism in treating psoriasis by electroacupuncture.