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Cell Death & Disease Mar 2023Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczema-like skin lesions, dry skin, severe itching, and recurrent recurrence. The whey...
Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by eczema-like skin lesions, dry skin, severe itching, and recurrent recurrence. The whey acidic protein four-disulfide core domain gene WFDC12 is highly expressed in skin tissue and up-regulated in the skin lesions of AD patients, but its role and relevant mechanism in AD pathogenesis have not been studied yet. In this study, we found that the expression of WFDC12 was closely related to clinical symptoms of AD and the severity of AD-like lesions induced by DNFB in transgenic mice. WFDC12-overexpressing in the epidermis might promote the migration of skin-presenting cells to lymph nodes and increase Th cell infiltration. Meanwhile, the number and ratio of immune cells and mRNA levels of cytokines were significantly upregulated in transgenic mice. In addition, we found that ALOX12/15 gene expression was upregulated in the arachidonic acid metabolism pathway, and the corresponding metabolite accumulation was increased. The activity of epidermal serine hydrolase decreased and the accumulation of platelet-activating factor (PAF) increased in the epidermis of transgenic mice. Collectively, our data demonstrate that WFDC12 may contribute to the exacerbation of AD-like symptoms in DNFB-induced mouse model by enhancing arachidonic acid metabolism and PAF accumulation and that WFDC12 may be a potential therapeutic target for human atopic dermatitis.
Topics: Animals; Mice; Humans; Dermatitis, Atopic; Platelet Activating Factor; Arachidonic Acid; Dinitrofluorobenzene; Skin; Proteins; Arachidonate 12-Lipoxygenase
PubMed: 36882395
DOI: 10.1038/s41419-023-05686-3 -
Frontiers in Molecular Biosciences 2023Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse...
Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.
PubMed: 36825199
DOI: 10.3389/fmolb.2023.1097955 -
Frontiers in Immunology 2022Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating...
Atopic dermatitis (AD) is a chronic inflammatory skin disease with significant health/economic burdens. Existing therapies are not fully effective, necessitating development of new approaches for AD management. Here, we report that dietary grape powder (GP) mitigates AD-like symptoms in 2,4-dinitrofluorobenzene (DNFB)-induced AD in NC/NgaTndCrlj mice. Using prevention and intervention protocols, we tested the efficacy of 3% and 5% GP-fortified diet in a 13-weeks study. We found that GP feeding markedly inhibited development and progression of AD-like skin lesions, and caused reduction in i) epidermal thickness, mast cell infiltration, ulceration, excoriation and acanthosis in dorsal skin, ii) spleen weight, extramedullary hematopoiesis and lymph nodes sizes, and iii) ear weight and IgE levels. We also found significant modulations in 15 AD-associated serum cytokines/chemokines. Next, using quantitative global proteomics, we identified 714 proteins. Of these, 68 (normal control) and 21 (5% GP-prevention) were significantly modulated (≥2-fold) vs AD control (DNFB-treated) group, with many GP-modulated proteins reverting to normal levels. Ingenuity pathway analysis of GP-modulated proteins followed by validation using ProteinSimple identified changes in acute phase response signaling (FGA, FGB, FGG, HP, HPX, LRG1). Overall, GP supplementation inhibited DNFB-induced AD in NC/NgaTndCrlj mice in both prevention and intervention trials, and should be explored further.
Topics: Mice; Animals; Dermatitis, Atopic; Vitis; Dinitrofluorobenzene; Skin Diseases; Diet
PubMed: 36741360
DOI: 10.3389/fimmu.2022.1051472 -
Inhibition of Mast Cell Degranulation in Atopic Dermatitis by Celastrol through Suppressing MRGPRX2.Disease Markers 2023Atopic dermatitis is a common dermatological disease, and mast cell degranulation is believed to be related with the progression of atopic dermatitis. Mas-related G...
BACKGROUND
Atopic dermatitis is a common dermatological disease, and mast cell degranulation is believed to be related with the progression of atopic dermatitis. Mas-related G protein-coupled receptor-X2 (MRGPRX2), and calcium release-activated calcium channel protein 1-2 (ORAI-1, ORAI-2) are involved in mast cell degranulation. Celastrol is an active monomer of Tripterygium wilfordii, and it presents an antiatopic role.
METHODS
2,4-Dinitrofluorobenzene (DNFB) and compound 48/80 (C 48/80) were used to establish a slow and acute scratching animal model, respectively. Hematoxylin-eosin and toluidine blue staining was used to investigate tissue injury. Inflammatory factor concentration was measured with ELISA. The expression of MRGPRX2, ORAI-1, and ORAI-2 was detected with immunohistochemistry (IHC) staining. Gene expression profiling and microRNA array were performed to investigate gene differential expression.
RESULTS
Celastrol greatly inhibited atopic dermatitis-related tissues injury, mast cell production, histamine release, scratching level, inflammatory factor expression, and activation of MRGPRX2/ORAI axis in the DNFB-induced atopic dermatitis model. The influence of Celastrol on atopic dermatitis was remarkably reversed by overexpression of MRGPRX2.
CONCLUSION
We found that the improvements of atopic dermatitis caused by Celastrol were reversed by treatment with MRGPRX2, indicating that Celastrol might affect atopic dermatitis through MRGPRX2. This study might provide a novel thought for the prevention and treatment of atopic dermatitis by regulating MRGPRX2.
Topics: Animals; Dermatitis, Atopic; Cell Degranulation; Mast Cells; Dinitrofluorobenzene; Receptors, Neuropeptide; Receptors, G-Protein-Coupled
PubMed: 36712922
DOI: 10.1155/2023/9049256 -
International Journal of Molecular... Dec 2022Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a...
Herein, we developed a dual-activated prodrug, BTC, that contains three functional components: a glutathione (GSH)-responsive BODIPY-based photosensitizer with a photoinduced electron transfer (PET) effect between BODIPY and the 2,4-dinitrobenzenesulfonate (DNBS) group, and an ROS-responsive thioketal linker connecting BODIPY and the chemotherapeutic agent camptothecin (CPT). Interestingly, CPT displayed low toxicity because the active site of CPT was modified by the BODIPY-based macrocycle. Additionally, BTC was encapsulated with the amphiphilic polymer DSPE-mPEG to improve drug solubility and tumor selectivity. The resulting nano-prodrug passively targeted tumor cells through enhanced permeability and retention (EPR) effects, and then the photosensitizing ability of the BODIPY dye was restored by removing the DNBS group with the high concentration of GSH in tumor cells. Light-triggered ROS from activated BODIPY can not only induce apoptosis or necrosis of tumor cells but also sever the thioketal linker to release CPT, achieving the combination treatment of selective photodynamic therapy and chemotherapy. The antitumor activity of the prodrug has been demonstrated in mouse mammary carcinoma 4T1 and human breast cancer MCF-7 cell lines and 4T1 tumor-bearing mice.
Topics: Humans; Mice; Animals; Female; Prodrugs; Breast Neoplasms; Reactive Oxygen Species; Nanoparticles; Photochemotherapy; Photosensitizing Agents; Cell Line, Tumor
PubMed: 36555298
DOI: 10.3390/ijms232415656 -
The Journal of Investigative Dermatology Jun 2023Regulatory T cells (Tregs) express CD73, an ectonucleotidase that converts adenosine (Ado) monophosphate to Ado, which has been shown to suppress immune reactions. To...
Regulatory T cells (Tregs) express CD73, an ectonucleotidase that converts adenosine (Ado) monophosphate to Ado, which has been shown to suppress immune reactions. To investigate the role(s) of CD73 Tregs during the induction of tolerance, we used a 2,4-dinitrofluorobenzene‒driven contact hypersensitivity model, in which tolerance can be induced by pretreating wild type mice with 2,4-dinitrothiocyanobenzene. CD73-deficient mice were unable to acquire tolerance. Likewise, transfer of CD73 Tregs failed to suppress 2,4-dinitrofluorobenzene‒induced ear swelling in wild type mice, whereas transfer of wild type‒derived Tregs into CD73 mice re-established tolerance. This indicates a crucial role of CD73 Tregs for skin-induced tolerance. Furthermore, we found that 2,4-dinitrothiocyanobenzene induces more activated CD73 tissue-homing Tregs (marked by Ki-67, CTLA4, CCR4, CD103, CCR6, and CD49b expression) in draining lymph nodes and blood, eventually accumulating in the skin. The application of anti-CD73 antibodies that block CD73-derived Ado production as well as the injection of Ado deaminase, which degrades Ado in tissues, abrogated tolerance induction. Thus, our data indicate that CD73 Ado-producing Tregs are crucial for the regulation of contact hypersensitivity reactions and tolerance induction in the skin and that manipulating the function(s) of CD73 in tissues may offer a tool to influence autoimmunity and inflammation in vivo.
Topics: Mice; Animals; T-Lymphocytes, Regulatory; Adenosine; Dinitrofluorobenzene; Dermatitis, Allergic Contact; Immune Tolerance; 5'-Nucleotidase
PubMed: 36539031
DOI: 10.1016/j.jid.2022.12.003 -
Drug Design, Development and Therapy 2022To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching,...
PURPOSE
To undercover the underlying mechanisms of luteolin against atopic dermatitis (AD), clinically characterized by recurrent eczematous lesions and intense itching, based on network pharmacology, molecular docking and in vivo experimental validation.
METHODS
TCMSP, STITCH and SwissTargetPrediction databases were utilized to screen the corresponding targets of luteolin. Targets related to AD were collected from DisGeNET, GeneCards and TTD databases. PPI network of intersection targets was constructed through STRING 11.0 database and Cytoscape 3.9.0 software. GO and KEGG enrichment analysis were performed to investigate the critical pathways of luteolin against AD. Further, the therapeutic effects and candidate targets/signaling pathways predicted from network pharmacology analysis were experimentally validated in a mouse model of AD induced by 2, 4-dinitrofluorobenzene (DNFB).
RESULTS
A total of 31 intersection targets were obtained by matching 151 targets of luteolin with 553 targets of AD. Among all, 20 core targets were identified by PPI network topology analysis, including IL-6, TNF, IL-10, VEGFA, IL-4, etc., and molecular docking indicated that luteolin binds strongly to these core targets. KEGG pathway enrichment analysis suggested that the intersected targets were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, Th1 and Th2 cell differentiation, JAK/STAT signaling pathway, etc. The in vivo experiment validated that luteolin could alleviate AD-like skin symptoms, as evidenced by the lower SCORAD score, the reduced infiltration of mast cells and the recovery of skin barrier function. Furthermore, luteolin restored immune balance by regulating the production of Th1/Th2/Th17-mediated cytokines, which were both the predicted core targets. Moreover, luteolin inhibited the phosphorylation of JAK2 and STAT3 in the lesional skin.
CONCLUSION
Together, the present study systematically clarifies the ameliorative effects and possible molecular mechanisms of luteolin against AD through the combination of network pharmacology and experimental validation, shedding light on the future development and clinical application of luteolin.
Topics: Animals; Mice; Luteolin; Dermatitis, Atopic; Molecular Docking Simulation; Network Pharmacology; Dinitrofluorobenzene; Drugs, Chinese Herbal
PubMed: 36530790
DOI: 10.2147/DDDT.S387893 -
BMC Immunology Dec 2022The progression of acute-to-chronic atopic dermatitis is accompanied by multiple helper T-cell cytokine responses, but the mechanisms and relative importance of these...
BACKGROUND
The progression of acute-to-chronic atopic dermatitis is accompanied by multiple helper T-cell cytokine responses, but the mechanisms and relative importance of these changes remain unclear. There is no animal model for atopic dermatitis that recapitulates these cytokine responses.
OBJECTIVE
We sought to build a novel mouse model for atopic dermatitis (AD) that recapitulates these helper T-cell responses and some dynamic changes in cytokine responses in the progression of AD.
METHODS
Female BALB/c mice were subjected to the application of dinitrofluorobenzene (DNFB) and ovalbumin (OVA) to induce AD-like dermatitis. Skin lesions and serum were collected from mice in the acute and chronic phases to detect changes in cytokine responses and other features of AD.
RESULTS
Combined application of DNFB and OVA successfully induced AD-like dermatitis and histological changes as well as epidermal barrier dysfunction. In the acute phase of AD-like dermatitis, Th2-associated cytokines were mainly increased in serum and skin lesions. In the chronic phase of AD-like dermatitis, Th2-associated cytokines were still highly expressed, while Th1- and Th17-associated cytokines were also gradually increased. Compared with the acute phase, the JAK-STAT signaling pathway was highly expressed in the chronic phase of AD-like dermatitis.
CONCLUSION
The combined application of DNFB and OVA could be used to build a new mouse model for atopic dermatitis. This mouse model recapitulates the helper T-cell responses and some dynamic changes in cytokine responses in the progression of acute-to-chronic in human AD. The JAK-STAT signaling pathway plays a pivotal role in the chronicity of AD.
Topics: Humans; Female; Mice; Animals; Dinitrofluorobenzene; Ovalbumin; Dermatitis, Atopic; Cytokines; T-Lymphocytes, Helper-Inducer
PubMed: 36476273
DOI: 10.1186/s12865-022-00531-2 -
Scientific Reports Nov 2022The only official method that can detect the skin sensitizing potential of chemicals, including the elicitation response, is the OECD test guideline (TG) 406. However,...
The only official method that can detect the skin sensitizing potential of chemicals, including the elicitation response, is the OECD test guideline (TG) 406. However, this guideline uses guinea pigs, which requires complex procedures. Since a simple and complete test method for evaluating skin sensitization is needed, especially for mechanistic studies of skin sensitization, this study confirmed the reactivity of mice to skin sensitizing substances. We set up a protocol involving one induction exposure of the test substance to the back skin, followed by three challenge exposures to the auricle (Protocol 2), and compared their skin sensitization responses with the results of two exposures to the auricle and back skin every 2 weeks (Protocol 1) and a local lymph node assay (TG442B). A hapten 2,4-dinitrofluorobenzene caused significant auricular thickening, skin inflammation, and enlarged auricular lymph nodes in Protocols 1 and 2. These changes were more pronounced in Protocol 2. Plasma IgE and IgG1 and gene expression of IL4, IFNγ, and perforin were significantly increased in Protocol 2. Cell proliferation in the auricular lymph nodes was observed in both protocols as in TG442B. These results indicate that Protocol 2 can be a good candidate for a relatively simple skin sensitization test.
Topics: Mice; Guinea Pigs; Animals; Skin Tests; Local Lymph Node Assay; Haptens; Dermatitis, Allergic Contact; Skin
PubMed: 36400912
DOI: 10.1038/s41598-022-24547-1 -
Pain Jun 2023Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch...
Novel proresolving lipid mediator mimetic 3-oxa-PD1n-3 docosapentaenoic acid reduces acute and chronic itch by modulating excitatory and inhibitory synaptic transmission and astroglial secretion of lipocalin-2 in mice.
Specialized proresolving mediators (SPMs) have demonstrated potent analgesic actions in animal models of pathological pain. The actions of SPMs in acute and chronic itch are currently unknown. Recently, n-3 docosapentaenoic acid (DPA) was found to be a substrate for the biosynthesis of several novel families of SPMs and 3-oxa-PD1 n-3 DPA (3-oxa-PD1) is an oxidation-resistant metabolic stable analogue of the n-3 DPA-derived protectin D1 (PD1). In this article, we demonstrate that 3-oxa-PD1 effectively reduces both acute and chronic itch in mouse models. Intrathecal injection of 3-oxa-PD1 (100 ng) reduced acute itch induced by histamine, chloroquine, or morphine. Furthermore, intrathecal 3-oxa-PD1 effectively reduced chronic itch, induced by cutaneous T-cell lymphoma (CTCL), allergic contact dermatitis with dinitrofluorobenzene, and psoriasis by imiquimod. Intratumoral injection of 3-oxa-PD1 also suppressed CTCL-induced chronic itch. Strikingly, the antipruritic effect lasted for several weeks after 1-week intrathecal 3-oxa-PD1 treatment. Whole-cell recordings revealed significant increase in excitatory postsynaptic currents in spinal dorsal horn (SDH) neurons of CTCL mice, but this increase was blocked by 3-oxa-PD1. 3-oxa-PD1 further increased inhibitory postsynaptic currents in SDH neurons of CTCL mice. Cutaneous T-cell lymphoma increased the spinal levels of lipocalin-2 (LCN2), an itch mediator produced by astrocytes. 3-oxa-PD1 suppressed LCN2 production in CTCL mice and LCN2 secretion in astrocytes. Finally, CTCL-induced anxiety was alleviated by intrathecal 3-oxa-PD1. Our findings suggest that 3-oxa-PD1 potently inhibits acute and chronic itch through the regulation of excitatory or inhibitory synaptic transmission and astroglial LCN2 production. Therefore, stable SPM analogs such as 3-oxa-PD1 could be useful to treat pruritus associated with different skin injuries.
Topics: Animals; Mice; Astrocytes; Fatty Acids, Unsaturated; Lipocalin-2; Lymphoma, T-Cell, Cutaneous; Mice, Inbred C57BL; Pruritus; Synaptic Transmission
PubMed: 36378290
DOI: 10.1097/j.pain.0000000000002824