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International Journal of Molecular... Oct 2020CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1 cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that...
CX3CL1 can function as both an adhesion molecule and a chemokine for CX3CR1 cells, such as T cells, monocytes, and NK cells. Recent studies have demonstrated that CX3CL1-CX3CR1 interaction is associated with the development of various inflammatory skin diseases. In this study, we examined CX3CR1 involvement in 2,4-dinitrofluorobenzene (DNFB)-induced contact hypersensitivity using CX3CR1 mice. Ear swelling and dermal edema were attenuated after DNFB challenge in CX3CR1 mice. Expression of TNF-α, IL-6, and M1 macrophage markers was decreased in the ears of CX3CR1 mice, whereas expression of M2 macrophage markers including arginase-1 was increased. Decreased TNF-α and IL-6 expression and increased arginase-1 expression were found in peritoneal macrophages from CX3CR1 mice. Furthermore, ear swelling was attenuated by depleting dermal macrophages in wild-type mice to a similar level to CX3CR1 mice. These results suggest that CX3CR1 deficiency could induce skewed polarization towards M2 phenotype in macrophages, resulting in attenuation of contact hypersensitivity response.
Topics: Animals; Biomarkers; CX3C Chemokine Receptor 1; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Disease Susceptibility; Immunohistochemistry; Macrophage Activation; Macrophages; Mice; Mice, Knockout; Neutrophil Infiltration
PubMed: 33036460
DOI: 10.3390/ijms21197401 -
International Journal of Molecular... Sep 2020Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that...
Caffeic acid (CA) is produced from a variety of plants and has diverse biological functions, including anti-inflammation activity. It has been recently demonstrated that caffeoyl-prolyl-histidine amide (CA-PH), which is CA conjugated with proline-histidine dipeptide, relieves atopic dermatitis (AD)-like phenotypes in mouse. In this study, we investigated the molecular mechanism underlying CA-PH-mediated alleviation of AD-like phenotypes using cell line and AD mouse models. We confirmed that CA-PH suppresses AD-like phenotypes, such as increased epidermal thickening, infiltration of mast cells, and dysregulated gene expression of cytokines. CA-PH suppressed up-regulation of cytokine expression through inhibition of nuclear translocation of NF-κB. Using a CA-PH affinity pull-down assay, we found that CA-PH binds to Fyn. In silico molecular docking and enzyme kinetic studies revealed that CA-PH binds to the ATP binding site and inhibits Fyn competitively with ATP. CA-PH further suppressed spleen tyrosine kinase (SYK)/inhibitor of nuclear factor kappa B kinase (IKK)/inhibitor of nuclear factor kappa B (IκB) signaling, which is required for nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. In addition, chronic application of CA-PH, in contrast with that of glucocorticoids, did not induce up-regulation of regulated in development and DNA damage response 1 (REDD1), reduction of mammalian target of rapamycin (mTOR) signaling, or skin atrophy. Thus, our study suggests that CA-PH treatment may help to reduce skin inflammation via down-regulation of NF-κB activation, and Fyn may be a new therapeutic target of inflammatory skin diseases, such as AD.
Topics: Amides; Animals; Anti-Inflammatory Agents; Atrophy; Caffeic Acids; Dermatitis, Atopic; Dinitrofluorobenzene; Dipeptides; Disease Models, Animal; Female; Gene Expression Regulation; Glycoconjugates; HaCaT Cells; Humans; I-kappa B Kinase; Mice; Mice, Inbred BALB C; Molecular Docking Simulation; NF-kappa B; Protein Binding; Proto-Oncogene Proteins c-fyn; Signal Transduction; Skin; Syk Kinase; TOR Serine-Threonine Kinases; Transcription Factors
PubMed: 32998341
DOI: 10.3390/ijms21197160 -
Immunity, Inflammation and Disease Dec 2020Mechanisms underlying skin sensitization in allergic contact dermatitis have been actively studied using the murine contact hypersensitivity (CHS) model. However, much...
INTRODUCTION
Mechanisms underlying skin sensitization in allergic contact dermatitis have been actively studied using the murine contact hypersensitivity (CHS) model. However, much less is known about sensitization at the vaginal mucosa (VM).
METHODS
We developed a CHS model with VM sensitization and epicutaneous elicitation at the ear. We then examined the proliferation activity of lymphocytes, the frequencies of T cells and the differentiation of hapten-specific T cells in draining lymph nodes (dLNs) after sensitization.
RESULTS
Hapten-specific CHS responses to 2,4-dinitrofluorobenzene (DNFB), 2,4,6-trinitrochrolobenzene, and oxazolone assessed by ear swelling suggested that the VM would be an inductive site of CHS to haptens. In the comparisons of CHS responses to each of the three haptens examined, the lower responses in VM-sensitized mice were observed than skin-sensitized mice (e.g., DNFB-induced responses, -56%; p < .001, at 48 h after challenge). Consistent with the CHS responses, the DNFB-induced proliferation of cells in dLNs examined by 5-bromo-2'-deoxyuridine assay was lower (-62%; p < .001) in VM-sensitized mice than skin-sensitized mice. On the other hand, between skin and VM sensitization, no significant differences were observed in the frequencies of interferon-γ-producing CD4 and CD8 effector, and regulatory T cells in dLNs after sensitization. We also observed no significant differences with respect to differentiation of hapten-specific T cells based on the examination of cytokine production from dLN cells stimulated in vitro with 2,4-dinitrobenzene sulfonate.
CONCLUSION
These findings suggested that the lower T cell proliferation after VM sensitization is important for the lower CHS responses with VM sensitization than skin sensitization.
Topics: Animals; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Female; Mice; Mice, Inbred C57BL; Mucous Membrane; Vagina
PubMed: 32914939
DOI: 10.1002/iid3.351 -
Scientific Reports Sep 2020Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently...
Suprabasin (SBSN) is expressed not only in epidermis but also in epithelial cells of the upper digestive tract where metals such as nickel are absorbed. We have recently shown that SBSN level is decreased in the stratum corneum and serum of atopic dermatitis (AD) patients, especially in intrinsic AD, which is characterized by metal allergy. By using SBSN-null (Sbsn) mice, this study was conducted to investigate the outcome of SBSN deficiency in relation to AD. Sbsn mice exhibited skin barrier dysfunction on embryonic day 16.5, but after birth, their barrier function was not perturbed despite the presence of ultrastructural changes in stratum corneum and keratohyalin granules. Sbsn mice showed a comparable ovalbumin-specific skin immune response to wild type (WT) mice and rather lower contact hypersensitivity (CHS) responses to haptens than did WT mice. The blood nickel level after oral feeding of nickel was significantly higher in Sbsn mice than in WT mice, and CHS to nickel was elevated in Sbsn mice under nickel-loading condition. Our study suggests that the completely SBSN deficient mice retain normal barrier function, but harbor abnormal upper digestive tract epithelium that promotes nickel absorption and high CHS to nickel, sharing the features of intrinsic AD.
Topics: Animals; Antigens, Differentiation; Dermatitis, Contact; Dinitrofluorobenzene; Embryo, Mammalian; Female; Mice; Mice, Inbred C57BL; Mice, Knockout; Nickel; Skin
PubMed: 32884021
DOI: 10.1038/s41598-020-71536-3 -
Journal of Microscopy and Ultrastructure 2020Contact dermatitis (CD) is considered among the common inflammatory skin diseases worldwide. Duchesne has antioxidant, anti-inflammatory, and antidepressant activity...
BACKGROUND
Contact dermatitis (CD) is considered among the common inflammatory skin diseases worldwide. Duchesne has antioxidant, anti-inflammatory, and antidepressant activity beside many other beneficial effects.
OBJECTIVES
This study aimed to assess the effect of pumpkin fruit extract in treating CD in mice exposed to chronic stress and to explore the mechanism through which pumpkin can relief these changes.
MATERIALS AND METHODS
Thirty male albino rats were divided into three groups ( = 10); the control and two experimental groups that were exposure to chronic unpredictable mild stress for 4 weeks then painting with 1-fluoro-2,4-dinitrofluorobenzene (DNFB) for 3 consecutive days/week for 2 weeks to induce CD. Biochemical assessment of corticosterone level and antioxidants activity was performed. Skin of affected areas was excised, processed for histopathological examination.
RESULTS
DNFB-induced CD presented with dryness, hardness, and scaling. There was a significant reduction ( < 0.001) in the levels of superoxide dismutase, glutathione peroxidase and catalase activity in the skin of rats had CD. Histopathologically, the shin showed hyperplastic-thickened epidermis, focal elongation of the rete ridges, inflammatory cells infiltration in the superficial dermis, and increased collagen fibers. Local administration of pumpkin extract significantly increased the antioxidants activity in the skin and alleviated the CD-associated changes.
CONCLUSIONS
This study showed that the pumpkin fruit extract could have a potential in treating CD in stressed conditions mainly via its enhancement of skin antioxidant activity.
PubMed: 32766119
DOI: 10.4103/JMAU.JMAU_37_19 -
International Journal of Molecular... Jul 2020Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features...
Inhalations with brine solutions are old but underestimated add-ons to pharmacological treatments of inflammatory lung diseases. Although widely used, not all features underlying their action on the respiratory system have been explored. The aim of the present study was to elucidate the mechanism of the beneficial action of inhalations of brine solution from the 'Wieliczka' Salt Mine, a Polish health resort, in a murine model of non-atopic asthma. Asthma was induced in BALB/c mice by skin sensitization with dinitrofluorobenzene followed by an intratracheal challenge of cognate hapten. All animals underwent 12 inhalation sessions with brine solution, pure water or physiological saline. Control mice were not inhaled. We found that brine inhalations reduced, as compared to non-inhaled mice, the typical asthma-related symptoms, like airway hyperreactivity (AHR), the infiltration of pro-inflammatory cells into the bronchial tree, and the inflammation of the airways at the level of pro-inflammatory cytokines IL-1α, IL-1β and IL-6. The level of the anti-inflammatory IL-10 was elevated in brine-inhaled mice. Inhalations with pure water increased AHR, whereas saline had no influence, either on AHR or cytokine concentrations. These observations indicate that inhalations with a brine solution from the 'Wieliczka' Salt Mine diminish the asthma-related symptoms, mostly by reducing the inflammatory status and by decreasing AHR.
Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Asthma; Bronchial Hyperreactivity; Cytokines; Dinitrofluorobenzene; Disease Models, Animal; Haptens; Inflammation; Lung; Male; Mice; Mice, Inbred BALB C; Salts
PubMed: 32645931
DOI: 10.3390/ijms21134798 -
Nutrients Jun 2020Contact hypersensitivity (CHS) is the most common occupational dermatological disease. Dendritic cells (DCs) mediate the sensitization stage of CHS, while T-cells...
Black Raspberries and Protocatechuic Acid Mitigate DNFB-Induced Contact Hypersensitivity by Down-Regulating Dendritic Cell Activation and Inhibiting Mediators of Effector Responses.
Contact hypersensitivity (CHS) is the most common occupational dermatological disease. Dendritic cells (DCs) mediate the sensitization stage of CHS, while T-cells facilitate the effector mechanisms that drive CHS. Black raspberry (, BRB) and BRB phytochemicals possess immunomodulatory properties, but their dietary effects on CHS are unknown. We examined the effects of diets containing BRB and protocatechuic acid (PCA, a constituent of BRB and an anthocyanin metabolite produced largely by gut microbes), on CHS, using a model induced by 2,4-dinitrofluorobenze (DNFB). Mice were fed control diet or diets supplemented with BRB or PCA. In vitro bone-marrow derived DCs and RAW264.7 macrophages were treated with BRB extract and PCA. Mice fed BRB or PCA supplemented diets displayed decreased DNFB-induced ear swelling, marked by decreased splenic DC accumulation. BRB extract diminished DC maturation associated with reduced expression and Interleukin (IL)-12 secretion, and PCA reduced IL-12. Dietary supplementation with BRB and PCA induced differential decreases in IL-12-driven CHS mediators, including Interferon (IFN)-γ and IL-17 production by T-cells. BRB extracts and PCA directly attenuated CHS-promoting macrophage activity mediated by nitric oxide and IL-12. Our results demonstrate that BRB and PCA mitigate CHS pathology, providing a rationale for CHS alleviation via dietary supplementation with BRB or BRB derived anthocyanins.
Topics: Animals; B7-1 Antigen; Dendritic Cells; Dermatitis, Contact; Dietary Supplements; Dinitrofluorobenzene; Disease Models, Animal; Hydroxybenzoates; Interferon-gamma; Interleukin-12; Interleukin-17; Mice; Mice, Inbred BALB C; Phytotherapy; Plant Extracts; RAW 264.7 Cells; Rubus; T-Lymphocytes
PubMed: 32517233
DOI: 10.3390/nu12061701 -
Evidence-based Complementary and... 2020Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and skin lesions. The exact cause of AD is not yet known and the available...
Atopic dermatitis (AD) is a common inflammatory skin disease characterized by intense pruritus and skin lesions. The exact cause of AD is not yet known and the available therapeutic strategies for AD are limited. is commonly used in traditional Chinese medicine as an herb for treating chronic itch. However, the mechanism underlying the antipruritic effects of is not well understood. In the present study, we investigated the antipruritic effect of locally administered ethyl acetate extract from (EAEFC) to 2,4-dinitrofluorobenzene- (DNFB-) induced AD in a mouse model. The scratching behavior, skin thickness, dermatitis score, weight, blood immunoglobulin E (IgE) level, and itch-related cytokine levels were subsequently monitored and evaluated. Results showed that EAEFC treatment attenuated the DNFB-induced AD-like symptoms by alleviating the skin lesions and decreasing the dermatitis score. Hematoxylin and eosin (H&E) and toluidine blue (TB) staining analyses demonstrated that EAEFC mitigated the DNFB-induced increase in skin thickness and prevented the infiltration of mast cells. Behavioral tests showed that EAEFC decreased the DNFB-induced acute and chronic scratching behaviors. Furthermore, EAEFC reduced the levels of itch-related cytokines, such as thymic stromal lymphopoietin (TSLP), interleukin- (IL-) 17, IL-33, and IL-31, and the DNFB-induced boost in serum IgE. Collectively, these results suggest that EAEFC is a potential therapeutic candidate for the treatment of chronic itch in AD.
PubMed: 32454868
DOI: 10.1155/2020/6981386 -
EBioMedicine May 2020Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In...
BACKGROUND
Since numerous pathological conditions are evoked by unwanted dendritic cell (DC) activity, therapeutic agents modulating DC functions are of great medical interest. In regenerative medicine, cellular secretomes have gained increasing attention and valuable immunomodulatory properties have been attributed to the secretome of γ-irradiated peripheral blood mononuclear cells (PBMCs). Potential effects of the PBMC secretome (PBMCsec) on key DC functions have not been elucidated so far.
METHODS
We used a hapten-mediated murine model of contact hypersensitivity (CH) to study the effects of PBMCsec on DCs in vivo. Effects of PBMCsec on human DCs were investigated in monocyte-derived DCs (MoDC) and ex vivo skin cultures. DCs were phenotypically characterised by transcriptomics analyses and flow cytometry. DC function was evaluated by cytokine secretion, antigen uptake, PBMC proliferation and T-cell priming.
FINDINGS
PBMCsec significantly alleviated tissue inflammation and cellular infiltration in hapten-sensitized mice. We found that PBMCsec abrogated differentiation of MoDCs, indicated by lower expression of classical DC markers CD1a, CD11c and MHC class II molecules. Furthermore, PBMCsec reduced DC maturation, antigen uptake, lipopolysaccharides-induced cytokine secretion, and DC-mediated immune cell proliferation. Moreover, MoDCs differentiated with PBMCsec displayed diminished ability to prime naïve CD4T-cells into T1 and T2 cells. Furthermore, PBMCsec modulated the phenotype of DCs present in the skin in situ. Mechanistically, we identified lipids as the main biomolecule accountable for the observed immunomodulatory effects.
INTERPRETATION
Together, our data describe DC-modulatory actions of lipids secreted by stressed PBMCs and suggest PBMCsec as a therapeutic option for treatment of DC-mediated inflammatory skin conditions.
FUNDING
This research project was supported by the Austrian Research Promotion Agency (Vienna, Austria; grant "APOSEC" 862068; 2015-2019) and the Vienna Business Agency (Vienna, Austria; grant "APOSEC to clinic" 2343727).
Topics: Adult; Animals; Antigens, CD1; Biomarkers; CD11c Antigen; Cell Differentiation; Cell Proliferation; Culture Media, Conditioned; Dendritic Cells; Dermatitis, Contact; Dinitrofluorobenzene; Female; Gamma Rays; Gene Expression; Histocompatibility Antigens Class II; Humans; Immunologic Factors; Lipids; Lipopolysaccharides; Mice; Monocytes; Primary Cell Culture; Skin; Th1 Cells; Th2 Cells; Tissue Culture Techniques
PubMed: 32403085
DOI: 10.1016/j.ebiom.2020.102774 -
Allergy Aug 2020
Topics: Animals; Dermatitis, Allergic Contact; Dinitrobenzenes; Dinitrofluorobenzene; Disease Models, Animal; Interleukins; Mice; Mice, Inbred BALB C
PubMed: 32145081
DOI: 10.1111/all.14260