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  • 1
    Online Resource
    Online Resource
    Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 23, No. 1 ( 2021-12-28), p. 288-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 23, No. 1 ( 2021-12-28), p. 288-
    Abstract: For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation. Thus, the emergence of further in-depth research into diverse groups of compounds capable of activating this receptor has prompted reconsideration of its use therapeutically. The aim of this review is to summarize the body of research surrounding AhR and its role in regulating inflammation. Specifically, evidence supporting the potential of targeting this receptor to modulate the immune response in inflammatory and autoimmune diseases will be highlighted. Additionally, the opportunities and challenges of developing AhR-based therapies to suppress inflammation will be discussed.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms23010288
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 2
    Online Resource
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    Altered Gut DNA virome diversity associated HMGB1 release regulates reactive Astrocytes-induced IL6 release preferably via TLR4-NFkB pathway in experimental Gulf War Illness
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 64.15-64.15
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 64.15-64.15
    Abstract: In a recent study, we showed that the gut DNA bacteriophage dysbiosis in Gulf War Illness (GWI) was strongly associated with compromised intestinal epithelial cell integrity, increased circulatory IL6 and neuroinflammation. The current study further investigates the mechanism of DNA bacteriophage-IL6 axis in neuroinflammation. Advancing the previous findings, we show that viral dysbiosis positively correlated with high mobility group box protein 1 (HMGB1; a damage-associated molecular pattern) expression and release in circulation following GWI induction in mice. The circulatory HMGB1 activated brain Astrocytes via altering brain endothelial tight junction proteins and crossing the blood-brain barrier. Interestingly, both in GWI mice and mouse primary Astrocytes cell culture showed an increased brain IL6 mRNA and subsequent protein expression. However, GWI mice treated with Ribavirin (used for partial gut viral sterility) showed decreased intestinal HMGB1 and brain IL6 expression. Mechanistically, HMGB1 activated innate immune response via IRAKs-IKKα-NFkB instead of either RAGE-MAPK or PI3K-mTOR pathway. Surprisingly, inhibition of RAGE or PI3K pathway in HMGB1 primed mouse Astrocyte cells showed a significant increase in IL6 expression and release suggesting NFkB activation as a preferential pathway in GWI-Astrocyte-induced IL6 release. In summary, GWI-associated gut viral dysbiosis associated intestinal HMGB1 release activates brain Astrocytes and IL6 release via toll-like receptor 4-NFkB dependent pathway, thus causing neuroinflammation in GWI. The above mechanism can form a basis for studying inflammation-associated neurocognitive abnormalities in GWI.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.64.15
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 3
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    Production of MHCII ‐expressing classical monocytes increases during aging in mice and humans
    Wiley ; 2022
    In:  Aging Cell Vol. 21, No. 10 ( 2022-10)
    Details
    In: Aging Cell, Wiley, Vol. 21, No. 10 ( 2022-10)
    Abstract: Aging is associated with increased monocyte production and altered monocyte function. Classical monocytes are heterogenous and a shift in their subset composition may underlie some of their apparent functional changes during aging. We have previously shown that mouse granulocyte‐monocyte progenitors (GMPs) produce “neutrophil‐like” monocytes (NeuMo), whereas monocyte‐dendritic cell progenitors (MDPs) produce monocyte‐derived dendritic cell (moDC)‐producing monocytes (DCMo). Here, we demonstrate that classical monocytes from the bone marrow of old male and female mice have higher expression of DCMo signature genes ( H2‐Aa , H2‐Ab1 , H2‐Eb1 , Cd74 ), and that more classical monocytes express MHCII and CD74 protein. Moreover, we show that bone marrow MDPs and classical monocytes from old mice yield more moDC. We also demonstrate higher expression of Aw112010 in old monocytes and that Aw112010 lncRNA activity regulates MHCII induction in macrophages, which suggests that elevated Aw112010 levels may underlie increased MHCII expression during monocyte aging. Finally, we show that classical monocyte expression of MHCII is also elevated during healthy aging in humans. Thus, aging‐associated changes in monocyte production may underlie altered monocyte function and have implications for aging‐associated disorders.
    Type of Medium: Online Resource
    ISSN: 1474-9718 , 1474-9726
    URL: Issue
    URL: Article
    DOI: 10.1111/acel.v21.10
    DOI: 10.1111/acel.13701
    Language: English
    Publisher: Wiley
    Publication Date: 2022
    detail.hit.zdb_id: 2099130-7
    SSG: 12
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  • 4
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    2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Gimap5 Expression to Ameliorate Concanavalin-Induced T Cell-Mediated Liver Injury
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 154.13-154.13
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 154.13-154.13
    Abstract: GTPase of the immune-associated protein 5 (Gimap5) has been implicated in immune cell maintenance and development. A mouse model comparable to autoimmune hepatitis in humans was used to study the alterations induced in the gene expression profile of immune cells upon administration of environmental toxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). In this study, we tested the hypothesis that TCDD is capable of modulating gene expression to ameliorate autoimmune hepatitis severity. Mice were injected intravenously with 12.5 mg/kg concanavalin A (ConA) and treated intraperitoneally one hour after challenge with vehicle or 10 μg/kg TCDD. TCDD-treated mice showed lower levels of liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as compared to vehicle-treated mice. Histopathological analysis revealed a reduction in liver damage in the TCDD-treated group as compared to the vehicle-treated control. Furthermore, flow cytometric analysis of liver-infiltrating mononuclear cells demonstrated that following treatment with TCDD, there was an increase in FoxP3+CD4+ Tregs as well as a decrease in proinflammatory Tbet+ Th1 and RORγt+ Th17 T helper cell subtypes after induction of the disease. Single cell RNA-sequencing was conducted on liver mononuclear cells to further assess the changes induced by TCDD. The gene expression profile showed that TCDD treatment significantly upregulated the expression of vital genes such as Gimap5, a maintenance gene for normal liver function and survival of T cells. In summary, our data suggests that TCDD is capable of inducing Gimap5 expression in autoimmune hepatitis, which in turn modulates the progression of this disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.154.13
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 5
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    Effects of Acute 2,3,7,8-Tetrachlorodibenzo-p-Dioxin Exposure on the Circulating and Cecal Metabolome Profile
    MDPI AG ; 2021
    In:  International Journal of Molecular Sciences Vol. 22, No. 21 ( 2021-10-30), p. 11801-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 22, No. 21 ( 2021-10-30), p. 11801-
    Abstract: 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a polyhalogenated planar hydrocarbon belonging to a group of highly toxic and persistent environmental contaminants known as “dioxins”. TCDD is an animal teratogen and carcinogen that is well characterized for causing immunosuppression through activation of aryl hydrocarbon receptor (AHR). In this study, we investigated the effect of exposure of mice to an acute dose of TCDD on the metabolic profile within the serum and cecal contents to better define the effects of TCDD on host physiology. Our findings demonstrated that within the circulating metabolome following acute TCDD exposure, there was significant dysregulation in the metabolism of bioactive lipids, amino acids, and carbohydrates when compared with the vehicle (VEH)-treated mice. These widespread changes in metabolite abundance were identified to regulate host immunity via modulating nuclear factor-kappa B (NF-κB) and extracellular signal-regulated protein kinase (ERK1/2) activity and work as biomarkers for a variety of organ injuries and dysfunctions that follow TCDD exposure. Within the cecal content of mice exposed to TCDD, we were able to detect changes in inflammatory markers that regulate NF-κB, markers of injury-related inflammation, and changes in lysine degradation, nicotinamide metabolism, and butanoate metabolism, which collectively suggested an immediate suppression of broad-scale metabolic processes in the gastrointestinal tract. Collectively, these results demonstrate that acute TCDD exposure results in immediate irregularities in the circulating and intestinal metabolome, which likely contribute to TCDD toxicity and can be used as biomarkers for the early detection of individual exposure.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms222111801
    Language: English
    Publisher: MDPI AG
    Publication Date: 2021
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 6
    Online Resource
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    Regulation of Intestinal Stem Cell Stemness by the Aryl Hydrocarbon Receptor and Its Ligands
    Frontiers Media SA ; 2021
    In:  Frontiers in Immunology Vol. 12 ( 2021-3-10)
    Details
    In: Frontiers in Immunology, Frontiers Media SA, Vol. 12 ( 2021-3-10)
    Abstract: Maintenance of intestinal homeostasis requires the integration of immunological and molecular processes together with environmental, diet, metabolic and microbial cues. Key to this homeostasis is the proper functioning of epithelial cells originating from intestinal stem cells (ISCs). While local factors and numerous molecular pathways govern the ISC niche, the conduit through which these processes work in concordance is the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, whose role in immunoregulation is critical at barrier surfaces. In this review, we discuss how AhR signaling is emerging as one of the critical regulators of molecular pathways involved in epithelial cell renewal. In addition, we examine the putative contribution of specific AhR ligands to ISC stemness and epithelial cell fate.
    Type of Medium: Online Resource
    ISSN: 1664-3224
    URL: Article
    DOI: 10.3389/fimmu.2021.638725
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2606827-8
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  • 7
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    Cannabinoid Receptor Activation on Haematopoietic Cells and Enterocytes Protects against Colitis
    Oxford University Press (OUP) ; 2021
    In:  Journal of Crohn's and Colitis Vol. 15, No. 6 ( 2021-06-22), p. 1032-1048
    Details
    In: Journal of Crohn's and Colitis, Oxford University Press (OUP), Vol. 15, No. 6 ( 2021-06-22), p. 1032-1048
    Abstract: Cannabinoid receptor [CB] activation can attenuate inflammatory bowel disease [IBD] in experimental models and human cohorts. However, the roles of the microbiome, metabolome, and the respective contributions of haematopoietic and non-haematopoietic cells in the anti-colitic effects of cannabinoids have yet to be determined. Methods Female C57BL/6 mice were treated with either cannabidiol [CBD], Δ 9-tetrahydrocannabinol [THC] , a combination of CBD and THC, or vehicle, in several models of chemically induced colitis. Clinical parameters of colitis were assessed by colonoscopy, histology, flow cytometry, and detection of serum biomarkers; single-cell RNA sequencing and qRT-PCR were used to evaluate the effects of cannabinoids on enterocytes. Immune cell transfer from CB2 knockout mice was used to evaluate the contribution of haematopoietic and non-haematopoietic cells to colitis protection. Results We found that THC prevented colitis and that CBD, at the dose tested, provided little benefit to the amelioration of colitis, nor when added synergistically with THC. THC increased colonic barrier integrity by stimulating mucus and tight junction and antimicrobial peptide production, and these effects were specific to the large intestine. THC increased colonic Gram-negative bacteria, but the anti-colitic effects of THC were independent of the microbiome. THC acted both on immune cells via CB2 and on enterocytes, to attenuate colitis. Conclusions Our findings demonstrate how cannabinoid receptor activation on both immune cells and colonocytes is critical to prevent colonic inflammation. These studies also suggest how cannabinoid receptor activation can be used as a preventive and therapeutic modality against colitis.
    Type of Medium: Online Resource
    ISSN: 1873-9946 , 1876-4479
    URL: Article
    DOI: 10.1093/ecco-jcc/jjaa253
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2021
    detail.hit.zdb_id: 2389631-0
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  • 8
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    Resveratrol mediates regulation of genes through microRNAs in the gut epithelial cells that may play a role in the gut health and amelioration of EAE in mice
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 69.2-69.2
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 69.2-69.2
    Abstract: Resveratrol (RES), found abundantly in red grapes, blue berries and peanuts, is an anti-inflammatory, anticancer, and antioxidant compound. We have previously shown that RES ameliorated EAE in mice regulating immune cell functions and differentiation. In this study, we investigated the effect of RES on gene expression in the gut epithelial cells of mice with EAE. To this end, epithelial cells from small intestine (SI) and colons of mice with EAE treated with vehicle or RES were isolated. Transcriptome arrays using total RNAs from epithelial cells of SI and colons were performed and data obtained from the arrays were analyzed using Transcriptome Analysis Console software. Results showed that there were 1,591 (1165 in SI and 426 in colon) genes that were up- or down-regulated ( & gt;2-fold) in the epithelial cells of mice with EAE treated with RES, when compared to vehicle. We selected two genes, α-defensins and Mucin 3, for further analysis. Upon analysis of their expression in the gut epithelial cells, α-defensins was downregulated in SI while Mucin 3 was upregulated in colon of EAE mice treated with RES. To understand the regulation of these two genes in the gut, we investigated the role of microRNAs (miRs). There were two miRs, miR-378 and miR-338, that showed strong binding affinity for α-defensins and Mucin 3 respectively. Upon analysis of their expression in epithelial cells, miR-378 was upregulated but miR-338 was downregulated, demonstrating their possible role in the regulation of α-defensins and Mucin 3 genes. Data obtained from this study demonstrates a possible role of miRs in the regulation of genes in the gut epithelial cells may play a role in improving the health of the gut and amelioration of EAE in mice.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.69.2
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 9
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    Functions and mechanisms of chondroitin disaccharide-induced miRNAs in the regulation of CD44 expression involved in the development of experimental autoimmune encephalomyelitis
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 1_Supplement ( 2020-05-01), p. 142.28-142.28
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 1_Supplement ( 2020-05-01), p. 142.28-142.28
    Abstract: Multiple sclerosis (MS) is a chronic demyelinating neurodegenerative disease of the central nervous system (CNS). In this study, we investigated the effects of chondroitin disaccharide and its induced miR-29b and miR-199b on CD44 expression in mouse lymphocytes, as well as the effects of miR-29b and miR-199b on the development and progression of experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of MS. The effects of chondroitin sulfate disaccharide on the changes in cellular immunity were investigated in EAE induced in mice by MOG and PTX. Real-time PCR and flow cytometry were used to investigate the effects of the anti-miRs and mimics of miR-29b and miR-199b on CD44 expression in mouse splenocytes after electroporation. After the transduction of antai-miRs and mimics of miR-29b and miR-199b into splenocytes, they were adoptively transferred into mice intravenously and the changes in immune cells and cytokines were analyzed by flow cytometry and ELISA. Our studies revealed that chondroitin disaccharide significantly up-regulated several specific miRNAs such as miR-29b and miR-199b, and thus dramatically inhibited EAE in mice. In vitro and in vivo studies demonstrated that miR-29b and miR-199b could down-regulate the expression of CD44 and modulate the expression of IL-17 and IL-4 in the lymphocytes from EAE mice. Therefore, miR-29b and miR-199b could inhibit the expression of CD44, modulate the expression of IL-4 and IL-17, and thus suppress lymphocyte proliferation and migration, leading to significant inhibition of EAE development. Thus, miR-29b and miR-199b could also be used as therapeutic targets for EAE and MS.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.204.Supp.142.28
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
    detail.hit.zdb_id: 1475085-5
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  • 10
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    Characterization of Altered Gene Expression and Histone Methylation in Peripheral Blood Mononuclear Cells Regulating Inflammation in COVID-19 Patients
    The American Association of Immunologists ; 2022
    In:  The Journal of Immunology Vol. 208, No. 8 ( 2022-04-15), p. 1968-1977
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 208, No. 8 ( 2022-04-15), p. 1968-1977
    Abstract: The pandemic of COVID-19 has caused & gt;5 million deaths in the world. One of the leading causes of the severe form of COVID-19 is the production of massive amounts of proinflammatory cytokines. Epigenetic mechanisms, such as histone/DNA methylation, miRNA, and long noncoding RNA, are known to play important roles in the regulation of inflammation. In this study, we investigated if hospitalized COVID-19 patients exhibit alterations in epigenetic pathways in their PBMCs. We also compared gene expression profiles between healthy controls and COVID-19 patients. Despite individual variations, the expressions of many inflammation-related genes, such as arginase 1 and IL-1 receptor 2, were significantly upregulated in COVID-19 patients. We also found the expressions of coagulation-related genes Von Willebrand factor and protein S were altered in COVID-19 patients. The expression patterns of some genes, such as IL-1 receptor 2, correlated with their histone methylation marks. Pathway analysis indicated that most of those dysregulated genes were in the TGF-β, IL-1b, IL-6, and IL-17 pathways. A targeting pathway revealed that the majority of those altered genes were targets of dexamethasone, which is an approved drug for COVID-19 treatment. We also found that the expression of bone marrow kinase on chromosome X, a member of TEC family kinases, was increased in the PBMCs of COVID-19 patients. Interestingly, some inhibitors of TEC family kinases have been used to treat COVID-19. Overall, this study provides important information toward identifying potential biomarkers and therapeutic targets for COVID-19 disease.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.2101099
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2022
    detail.hit.zdb_id: 1475085-5
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