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Journal of Immunology (Baltimore, Md. :... Feb 2022Calcitonin gene-related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17...
Calcitonin gene-related peptide (CGRP) can bias the outcome of Ag presentation to responsive T cells in vitro away from Th1-type immunity and toward the Th2 and Th17 poles through actions on endothelial cells (ECs). To test the in vivo significance of this observation, we engineered a mouse lacking functional CGRP receptors on ECs (EC receptor activity modifying protein 1 [RAMP1] knockout mice). On percutaneous immunization to 1-fluoro-2,4-dinitrobenzene, stimulated CD4 T cells from draining lymph nodes showed significantly reduced IL-17A expression with significantly increased IFN-γ, IL-4, and IL-22 expression at the protein and mRNA levels compared with control mice. Retinoic acid receptor-related orphan receptor γ t mRNA was significantly reduced, while mRNAs for T-box expressed in T cells and GATA binding protein 3 were significantly increased. In addition, EC RAMP1 knockout mice had significantly reduced contact hypersensitivity responses, and systemic administration of a CGRP receptor antagonist similarly inhibited contact hypersensitivity in wild-type mice. These observations provide compelling evidence that CGRP is a key regulator of cutaneous immunity through effects on ECs and suggest a novel pathway for potential therapeutic manipulation.
Topics: Animals; Antigen Presentation; Calcitonin Gene-Related Peptide; Dermatitis, Contact; Dinitrofluorobenzene; Endothelial Cells; GATA3 Transcription Factor; Interferon-gamma; Interleukin-17; Interleukin-4; Interleukins; Mice; Mice, Inbred C57BL; Mice, Knockout; Nuclear Receptor Subfamily 1, Group F, Member 1; Receptor Activity-Modifying Protein 1; Skin; Th1 Cells; Th17 Cells; Th2 Cells; Interleukin-22
PubMed: 35031579
DOI: 10.4049/jimmunol.2100139 -
Clinical and Experimental Immunology Feb 2013Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-immunoglobulin (Ig) has immunosuppressive properties both in vivo and in vitro, but much is still unknown about the...
Local and systemic effects of co-stimulatory blockade using cytotoxic T lymphocyte antigen-4-immunoglobulin in dinitrofluorobenzene- and oxazolone-induced contact hypersensitivity in mice.
Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4)-immunoglobulin (Ig) has immunosuppressive properties both in vivo and in vitro, but much is still unknown about the mechanisms by which CTLA-4-Ig exerts its immunosuppressive activities in vivo. The aim of this study was to investigate the effect of CTLA-4-Ig in a mouse model of contact hypersensitivity (CHS). The inflammatory response in the presence or absence of CTLA-4-Ig was evaluated by measuring the increase in ear thickness in sensitized animals after challenge. We observed a dose-dependent suppression of the ear swelling in both dinitrofluorobenzene (DNFB)- and oxazolone-induced CHS. The suppressive effect was still present 3 weeks after administration, even in the absence of circulating levels of CTLA-4-Ig. It was further shown that CTLA-4-Ig inhibits activation of T cells in the draining lymph node after sensitization and affects the maturation level of both dendritic cells and B cells. Furthermore, CTLA-4-Ig reduces infiltration of activated CD8(+) T cells into the inflamed ear tissue and suppresses both local and systemic inflammation, as illustrated by reduced expression of cytokines and chemokines in the inflamed ear and a reduced level of acute-phase proteins in circulation. Finally, our results suggest that CTLA-4-Ig has a mainly immunosuppressive effect during the sensitization phase. We conclude that CTLA-4-Ig induces long-term immunosuppression of both DNFB- and oxazolone-induced inflammation and our data are the first to compare the effect of this compound in both DNFB- and oxazolone-induced CHS and to show that CTLA-4-Ig exerts an immunosuppressive effect on both local and systemic inflammatory mediators which is mediated principally during the sensitization phase.
Topics: Abatacept; Animals; Cells, Cultured; Cytokines; Dermatitis, Contact; Dinitrofluorobenzene; Disease Models, Animal; Female; Humans; Immune Tolerance; Immunization; Immunoconjugates; Immunotherapy; Inflammation Mediators; Mice; Mice, Inbred BALB C; Oxazolone; Protein Binding; Receptor Cross-Talk
PubMed: 23286949
DOI: 10.1111/cei.12005 -
Computational and Mathematical Methods... 2022Allergic contact dermatitis (ACD) is a form of chronic cutaneous inflammatory disease of immunological origin that has adverse impacts on patient quality of life,...
BACKGROUND
Allergic contact dermatitis (ACD) is a form of chronic cutaneous inflammatory disease of immunological origin that has adverse impacts on patient quality of life, underscoring the need for the development of safe and effective therapeutic agents to treat affected individuals. Fisetin is a Chinese herbal preparation that reportedly exhibits antitumor, antioxidant, antimicrobial, anticoagulatory, and antimalarial activity. In the current report, the immunomodulatory activity of fisetin was appraised by assessing its impact on balance between regulatory T (Treg) and Th17 cells in an ACD model.
METHODS
BALB/c mice ( = 60) were randomized into control, ACD model, CTX positive control (20 mg/kg), and fisetin treatment groups (three dose levels: 2, 4, or 8 mg/kg). ACD induction was achieved by sensitizing mice on the shaved ventral abdomen via the application of 5% DNFB (50 L) on days 1 and 2, followed by rechallenge in the right ear with 5% DNFB (20 L) on day 5. Beginning on day 1, immunized mice were intraperitoneally injected with the appropriate fisetin dose (in saline) once per day for 7 days. On day 7, ear swelling, transcription factor expression, Th17/Treg cell populations, and cytokine production were assessed in vivo.
RESULTS
Fisetin treatment significantly suppressed ear swelling and associated inflammatory cell infiltration, besides reducing the production of Th17 cytokines (IL-17, TNF-, and IL-6) and the expression of the Th17 lineage transcription factor RORt while simultaneously enhancing Treg-specific cytokine production (TGF- and IL-10) and the expression of the Treg lineage transcription factor Foxp3, thereby restoring the Th17/Treg cell in ACD mice.
CONCLUSIONS
These data indicate that fisetin exhibits immunomodulatory activity and can alter the Th17/Treg cell balance, highlighting its potential value as a treatment drug for ACD.
Topics: Animals; Cytokines; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Flavonols; Humans; Mice; Mice, Inbred BALB C; Quality of Life; T-Lymphocytes, Regulatory; Th17 Cells; Transcription Factors
PubMed: 35437448
DOI: 10.1155/2022/9222541 -
The Journal of Investigative Dermatology Aug 1983
Topics: Animals; Dermatitis, Contact; Dinitrofluorobenzene; Immunity; Langerhans Cells; Mice; PUVA Therapy; Picryl Chloride; Skin; Skin Neoplasms; Ultraviolet Rays
PubMed: 6875303
DOI: 10.1111/1523-1747.ep12542059 -
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 -
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 -
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 -
Biomolecules Aug 2022Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in...
Similar to canine inflammatory enteropathy, inflammatory bowel disease (IBD) is a chronic idiopathic condition characterized by remission periods and recurrent flares in which diarrhea, visceral pain, rectal bleeding/bloody stools, and weight loss are the main clinical symptoms. Intestinal barrier function alterations often persist in the remission phase of the disease without ongoing inflammatory processes. However, current therapies include mainly anti-inflammatory compounds that fail to promote functional symptoms-free disease remission, urging new drug discoveries to handle patients during this step of the disease. ALIAmides (ALIA, autacoid local injury antagonism) are bioactive fatty acid amides that recently gained attention because of their involvement in the control of inflammatory response, prompting the use of these molecules as plausible therapeutic strategies in the treatment of several chronic inflammatory conditions. N-palmitoyl-D-glucosamine (PGA), an under-researched ALIAmide, resulted in being safe and effective in preclinical models of inflammation and pain, suggesting its potential engagement in the treatment of IBD. In our study, we demonstrated that micronized PGA significantly and dose-dependently reduces colitis severity, improves intestinal mucosa integrity by increasing the tight junction proteins expression, and downregulates the TLR-4/NLRP3/iNOS pathway via PPAR-α receptors signaling in DNBS-treated mice. The possibility of clinically exploiting micronized PGA as support for the treatment and prevention of inflammation-related changes in IBD patients would represent an innovative, effective, and safe strategy.
Topics: Animals; Dogs; Mice; Colitis; Dinitrofluorobenzene; Glucosamine; Inflammation; Inflammatory Bowel Diseases; NLR Family, Pyrin Domain-Containing 3 Protein; PPAR alpha; Toll-Like Receptor 4
PubMed: 36009057
DOI: 10.3390/biom12081163 -
Journal of the National Medical... Nov 1988The effects of trace metal contaminants (lead, cadmium, and mercury) on the immunologic responses of rats infected with Trypanosoma lewisi were investigated to determine... (Review)
Review
The effects of trace metal contaminants (lead, cadmium, and mercury) on the immunologic responses of rats infected with Trypanosoma lewisi were investigated to determine whether chronic exposures to subclinical levels of these metals have adverse effects on the host's ability to respond to an infective agent.Earlier and higher levels of parasitemia were detected in animals exposed to cadmium, lead, and mercury. The variability in length of trypanosome cells in metal-exposed animals became constant at a later time and persisted for a longer time, indicating a delay in antibody synthesis. Serum levels of IgG and IgM were increased in infected animals exposed to trace metals; however, lower levels were observed when compared with infected control animals. Animals exposed only to trace metals showed decreases in serum levels of IgG and IgM. In contact sensitivity to dinitrofluorobenzene (DNFB), animals exposed to trace metals demonstrated no significant difference in sensitization when compared with those infected and exposed to trace metals.
Topics: Animals; Cadmium; Dinitrofluorobenzene; Female; Immunodiffusion; Immunoelectrophoresis; Lead; Mercury; Rats; Rats, Inbred Strains; Trace Elements; Trypanosoma lewisi; Trypanosomiasis
PubMed: 3150464
DOI: No ID Found -
Immunity Sep 2008Oral tolerance prevents oral sensitization to dietary antigens (Ags), including proteins and haptens, and development of delayed-type hypersensitivity (DTH) responses....
Oral tolerance prevents oral sensitization to dietary antigens (Ags), including proteins and haptens, and development of delayed-type hypersensitivity (DTH) responses. We showed here that plasmacytoid dendritic cells (pDCs) prevented oral T cell priming and were responsible for systemic tolerance to CD4(+) and CD8(+) T cell-mediated DTH responses induced by Ag feeding. Systemic depletion of pDCs prevented induction of tolerance by antigen feeding. Transfer of oral Ag-loaded liver pDCs to naive recipient mice induced Ag-specific suppression of CD4(+) and CD8(+) T cell responses to protein and hapten, respectively. Liver is a site of oral Ag presentation, and pDCs appeared to induce anergy or deletion of Ag-specific T cells in the liver relatively rapidly via a CD4(+) T cell-independent mechanism. These data demonstrate that oral tolerance relies on Ag presentation by pDC to T cells and suggest that pDC could represent a key therapeutic target for intestinal and systemic inflammatory diseases.
Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Dendritic Cells; Dinitrofluorobenzene; Female; Hypersensitivity, Delayed; Immune Tolerance; Liver; Lymph Nodes; Mice; Mice, Inbred C57BL; Mouth Mucosa; Spleen
PubMed: 18789731
DOI: 10.1016/j.immuni.2008.06.017