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1.
Int J Mol Sci ; 25(4)2024 Feb 18.
Article in English | MEDLINE | ID: mdl-38397081

ABSTRACT

We previously reported that an aryl hydrocarbon receptor (AhR) ligand, indole-3-carbinol (I3C), was effective at reducing colitis severity through immune cell-mediated interleukin-22 (IL-22) production. Intestinal epithelial cells (IECs) are also involved in regulating colitis, so we investigated their AhR-mediated mechanisms in the current report. A transcriptome analysis of IECs in wildtype (WT) mice revealed that during colitis, I3C regulated select mucin proteins, which could be attributed to goblet cell development. To address this, experiments under in vivo colitis (mice) or in vitro colon organoid conditions were undertaken to determine how select mucin proteins were altered in the absence or presence of AhR in IECs during I3C treatment. Comparing WT to IEC-specific AhR knockout mice (AhRΔIEC), the results showed that AhR expression was essential in IECs for I3C-mediated protection during colitis. AhR-deficiency also impaired mucin protein expression, particularly mucin 2 (Muc2), independently of IL-22. Collectively, this report highlights the important role of AhR in direct regulation of Muc2. These results provide justification for future studies aimed at determining how AhR might regulate select mucins through mechanisms such as direct transcription binding to enhance production.


Subject(s)
Colitis , Receptors, Aryl Hydrocarbon , Animals , Mice , Mucin-2/genetics , Receptors, Aryl Hydrocarbon/metabolism , Interleukin-22 , Colitis/genetics , Mucins/genetics , Mice, Inbred C57BL
2.
iScience ; 25(9): 104994, 2022 Sep 16.
Article in English | MEDLINE | ID: mdl-36093055

ABSTRACT

While blockade of cannabinoid receptor 1 (CB1) has been shown to attenuate diet-induced obesity (DIO), its relative role in different cell types has not been tested. The current study investigated the role of CB1 in immune vs non-immune cells during DIO by generating radiation-induced bone marrow chimeric mice that expressed functional CB1 in all cells except the immune cells or expressed CB1 only in immune cells. CB1-/- recipient hosts were resistant to DIO, indicating that CB1 in non-immune cells is necessary for induction of DIO. Interestingly, chimeras with CB1-/- in immune cells showed exacerbation in DIO combined with infiltration of bone-marrow-derived macrophages to the brain and visceral adipose tissue, elevated food intake, and increased glucose intolerance. These results demonstrate the opposing role of CB1 in hematopoietic versus non-hematopoietic cells during DIO and suggests that targeting immune CB1 receptors provides a new pathway to ameliorate obesity and related metabolic disorders.

3.
Cells ; 10(12)2021 11 25.
Article in English | MEDLINE | ID: mdl-34943813

ABSTRACT

Acute respiratory distress syndrome (ARDS) is a serious lung condition characterized by severe hypoxemia leading to limitations of oxygen needed for lung function. In this study, we investigated the effect of anandamide (AEA), an endogenous cannabinoid, on Staphylococcal enterotoxin B (SEB)-mediated ARDS in female mice. Single-cell RNA sequencing data showed that the lung epithelial cells from AEA-treated mice showed increased levels of antimicrobial peptides (AMPs) and tight junction proteins. MiSeq sequencing data on 16S RNA and LEfSe analysis demonstrated that SEB caused significant alterations in the microbiota, with increases in pathogenic bacteria in both the lungs and the gut, while treatment with AEA reversed this effect and induced beneficial bacteria. AEA treatment suppressed inflammation both in the lungs as well as gut-associated mesenteric lymph nodes (MLNs). AEA triggered several bacterial species that produced increased levels of short-chain fatty acids (SCFAs), including butyrate. Furthermore, administration of butyrate alone could attenuate SEB-mediated ARDS. Taken together, our data indicate that AEA treatment attenuates SEB-mediated ARDS by suppressing inflammation and preventing dysbiosis, both in the lungs and the gut, through the induction of AMPs, tight junction proteins, and SCFAs that stabilize the gut-lung microbial axis driving immune homeostasis.


Subject(s)
Arachidonic Acids/therapeutic use , Endocannabinoids/therapeutic use , Gastrointestinal Microbiome , Gastrointestinal Tract/pathology , Lung/pathology , Polyunsaturated Alkamides/therapeutic use , Respiratory Distress Syndrome/drug therapy , Respiratory Distress Syndrome/microbiology , Animals , Antimicrobial Peptides/metabolism , Arachidonic Acids/pharmacology , Butyrates/metabolism , Cecum/pathology , Cell Separation , Colon/drug effects , Colon/pathology , Discriminant Analysis , Dysbiosis/complications , Dysbiosis/microbiology , Endocannabinoids/pharmacology , Enterotoxins , Female , Gastrointestinal Tract/drug effects , Lymph Nodes/drug effects , Lymph Nodes/pathology , Lymphocyte Activation/drug effects , Mice, Inbred C57BL , Pneumonia/drug therapy , Pneumonia/microbiology , Polyunsaturated Alkamides/pharmacology , Respiratory Distress Syndrome/complications , T-Lymphocytes/drug effects
4.
Front Immunol ; 12: 684727, 2021.
Article in English | MEDLINE | ID: mdl-34267755

ABSTRACT

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates T cell function. The aim of this study was to investigate the effects of AhR ligands, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), and 6-Formylindolo[3,2-b]carbazole (FICZ), on gut-associated microbiota and T cell responses during delayed-type hypersensitivity (DTH) reaction induced by methylated bovine serum albumin (mBSA) in a mouse model. Mice with DTH showed significant changes in gut microbiota including an increased abundance of Bacteroidetes and decreased Firmicutes at the phylum level. Also, there was a decrease in Clostridium cluster XIV and IV, which promote anti-inflammatory responses, and an increase in Prevotella copri that facilitates pro-inflammatory responses. Interestingly, treatment of mice with TCDD attenuated the DTH response, induced Tregs, suppressed Th17 cells in the mesenteric lymph nodes (MLNs), and reversed the gut microbiota composition toward normalcy. In contrast, FICZ exacerbated the DTH response, induced heightened Th17 cells, and failed to cause a major shift in gut microbiota. Furthermore, TCDD but not FICZ caused an increase in the levels of short-chain fatty acids (SCFA), n-butyric acid, and acetic acid. Administration of sodium butyrate into mice with DTH suppressed the response, increased Tregs, and reduced Th17 cells IL17. Butyrate also caused an increase in the abundance of Clostridium and a decrease in Prevotella. Lastly, TCDD, as well as butyrate but not FICZ, were able to inhibit proinflammatory Histone deacetylases (HDACs) class I and II. Together, our data suggest that AhR ligands, such as TCDD that suppress DTH response, may mediate this effect by reversing the gut dysbiosis induced during this inflammatory response, while FICZ may fail to suppress the DTH response because of its inability to overturn the dysbiosis.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/agonists , Gastrointestinal Microbiome/drug effects , Hypersensitivity, Delayed/metabolism , Receptors, Aryl Hydrocarbon/agonists , T-Lymphocytes, Regulatory/drug effects , Th17 Cells/drug effects , Animals , Basic Helix-Loop-Helix Transcription Factors/metabolism , Butyric Acid/pharmacology , Carbazoles/toxicity , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Female , Hypersensitivity, Delayed/genetics , Hypersensitivity, Delayed/immunology , Hypersensitivity, Delayed/prevention & control , Ligands , Mice , Mice, Inbred C57BL , Polychlorinated Dibenzodioxins/toxicity , Receptors, Aryl Hydrocarbon/metabolism , T-Lymphocytes, Regulatory/immunology , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
5.
J Crohns Colitis ; 15(6): 1032-1048, 2021 Jun 22.
Article in English | MEDLINE | ID: mdl-33331878

ABSTRACT

BACKGROUND AND AIMS: 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.


Subject(s)
Cannabidiol/pharmacology , Colitis , Dronabinol/pharmacology , Enterocytes , Immunity, Cellular , Receptor, Cannabinoid, CB2 , Animals , Cannabinoid Receptor Agonists/pharmacology , Colitis/chemically induced , Colitis/metabolism , Colitis/pathology , Colitis/therapy , Colonoscopy/methods , Drug Monitoring , Enterocytes/drug effects , Enterocytes/metabolism , Enterocytes/pathology , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Immunity, Cellular/drug effects , Immunity, Cellular/physiology , Mice , Mice, Inbred C57BL , Mice, Knockout , Protective Agents/pharmacology , Receptor, Cannabinoid, CB2/genetics , Receptor, Cannabinoid, CB2/metabolism
6.
Front Immunol ; 12: 815840, 2021.
Article in English | MEDLINE | ID: mdl-35058939

ABSTRACT

Post-traumatic stress disorder (PTSD) is a psychiatric disorder and patients diagnosed with PTSD often express other comorbid health issues, particularly autoimmune and inflammatory disorders. Our previous reports investigating peripheral blood mononuclear cells (PBMCs) from PTSD patients showed that these patients exhibit an increased inflammatory T helper (Th) cell phenotype and widespread downregulation of microRNAs (miRNAs), key molecules involved in post-transcriptional gene regulation. A combination of analyzing prior datasets on gene and miRNA expression of PBMCs from PTSD and Control samples, as well as experiments using primary PBMCs collected from human PTSD and Controls blood, was used to evaluate TP53 expression, DNA methylation, and miRNA modulation on Th17 development. In the current report, we note several downregulated miRNAs were linked to tumor protein 53 (TP53), also known as p53. Expression data from PBMCs revealed that compared to Controls, PTSD patients exhibited decreased TP53 which correlated with an increased inflammatory Th17 phenotype. Decreased expression of TP53 in the PTSD population was shown to be associated with an increase in DNA methylation in the TP53 promotor region. Lastly, the most significantly downregulated TP53-associated miRNA, let-7a, was shown to negatively regulate Th17 T cells. Let-7a modulation in activated CD4+ T cells was shown to influence Th17 development and function, via alterations in IL-6 and IL-17 production, respectively. Collectively, these studies reveal that PTSD patients could be susceptible to inflammation by epigenetic dysregulation of TP53, which alters the miRNA profile to favor a proinflammatory Th17 phenotype.


Subject(s)
Gene Expression Regulation , MicroRNAs/genetics , Stress Disorders, Post-Traumatic/etiology , Stress Disorders, Post-Traumatic/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism , Tumor Suppressor Protein p53/genetics , Adult , Biomarkers , DNA Methylation , Female , Humans , Immunophenotyping , Leukocytes, Mononuclear/immunology , Leukocytes, Mononuclear/metabolism , Lymphocyte Activation , Male , Middle Aged , Phenotype , Promoter Regions, Genetic , RNA Interference , Severity of Illness Index , Stress Disorders, Post-Traumatic/diagnosis , Tumor Suppressor Protein p53/metabolism
7.
Int J Mol Sci ; 21(24)2020 Dec 17.
Article in English | MEDLINE | ID: mdl-33348596

ABSTRACT

Aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is a potent ligand for AhR and a known carcinogen. While AhR activation by TCDD leads to significant immunosuppression, how this translates into carcinogenic signal is unclear. Recently, we demonstrated that activation of AhR by TCDD in naïve C57BL6 mice leads to massive induction of myeloid derived-suppressor cells (MDSCs). In the current study, we investigated the role of the gut microbiota in TCDD-mediated MDSC induction. TCDD caused significant alterations in the gut microbiome, such as increases in Prevotella and Lactobacillus, while decreasing Sutterella and Bacteroides. Fecal transplants from TCDD-treated donor mice into antibiotic-treated mice induced MDSCs and increased regulatory T-cells (Tregs). Injecting TCDD directly into antibiotic-treated mice also induced MDSCs, although to a lesser extent. These data suggested that TCDD-induced dysbiosis plays a critical role in MDSC induction. Interestingly, treatment with TCDD led to induction of MDSCs in the colon and undetectable levels of cysteine. MDSCs suppressed T cell proliferation while reconstitution with cysteine restored this response. Lastly, blocking CXC chemokine receptor 2 (CXCR2) impeded TCDD-mediated MDSC induction. Our data demonstrate that AhR activation by TCDD triggers dysbiosis which, in turn, regulates, at least in part, induction of MDSCs.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/metabolism , Dysbiosis/chemically induced , Gastrointestinal Microbiome/drug effects , Myeloid-Derived Suppressor Cells/metabolism , Polychlorinated Dibenzodioxins/adverse effects , Receptors, Aryl Hydrocarbon/metabolism , Receptors, Interleukin-8B/metabolism , Signal Transduction/drug effects , Animals , Anti-Bacterial Agents/pharmacology , Cells, Cultured , DNA, Bacterial/genetics , Fecal Microbiota Transplantation/methods , Feces/microbiology , Female , Gastrointestinal Microbiome/genetics , Mice , Mice, Inbred C57BL , Phylogeny , T-Lymphocytes, Regulatory/immunology
8.
J Clin Med ; 9(6)2020 Jun 09.
Article in English | MEDLINE | ID: mdl-32526927

ABSTRACT

Inflammatory bowel disease (IBD) is known to significantly increase the risk for development of colorectal cancer (CRC), suggesting inflammation and cancer development are closely intertwined. Thus, agents that suppress inflammation may prevent the onset of cancer. In the current study, we used resveratrol, an anti-inflammatory stilbenoid, to study the role of microbiota in preventing inflammation-driven CRC. Resveratrol treatment in the azoxymethane (AOM) and dextran sodium sulphate (DSS) CRC murine model caused an increase in anti-inflammatory CD4 + FOXP3 + (Tregs) and CD4 + IL10 + cells, a decrease in proinflammatory Th1 and Th17 cells, and attenuated CRC development. Gut microbial profile studies demonstrated that resveratrol altered the gut microbiome and short chain fatty acid (SCFA), with modest increases in n-butyric acid and a potential butyrate precursor isobutyric acid. Fecal transfer from resveratrol-treated CRC mice and butyrate supplementation resulted in attenuation of disease and suppression of the inflammatory T cell response. Data also revealed both resveratrol and sodium butyrate (BUT) were capable of inhibiting histone deacetylases (HDACs), correlating with Treg induction. Analysis of The Cancer Genome Atlas (TCGA) datasets revealed increased expression of Treg-specific transcription factor FoxP3 or anti-inflammatory IL-10 resulted in an increase in 5-year survival of patients with CRC. These data suggest that alterations in the gut microbiome lead to an anti-inflammatory T cell response, leading to attenuation of inflammation-driven CRC.

9.
JCI Insight ; 5(1)2020 01 16.
Article in English | MEDLINE | ID: mdl-31941837

ABSTRACT

Colitis, an inflammatory bowel disease, is caused by a variety of factors, but luminal microbiota are thought to play crucial roles in disease development and progression. Indole is produced by gut microbiota and is believed to protect the colon from inflammatory damage. In the current study, we investigated whether indole-3-carbinol (I3C), a naturally occurring plant product found in numerous cruciferous vegetables, can prevent colitis-associated microbial dysbiosis and attempted to identify the mechanisms. Treatment with I3C led to repressed colonic inflammation and prevention of microbial dysbiosis caused by colitis, increasing a subset of gram-positive bacteria known to produce butyrate. I3C was shown to increase production of butyrate, and when mice with colitis were treated with butyrate, there was reduced colonic inflammation accompanied by suppression of Th17 and induction of Tregs, protection of the mucus layer, and upregulation in Pparg expression. Additionally, IL-22 was increased only after I3C but not butyrate administration, and neutralization of IL-22 prevented the beneficial effects of I3C against colitis, as well as blocked I3C-mediated dysbiosis and butyrate induction. This study suggests that I3C attenuates colitis primarily through induction of IL-22, which leads to modulation of gut microbiota that promote antiinflammatory butyrate.


Subject(s)
Colitis/prevention & control , Dysbiosis/prevention & control , Indoles/pharmacology , Interleukins/metabolism , Animals , Butyric Acid/metabolism , Butyric Acid/pharmacology , Colitis/metabolism , Colitis/pathology , Colon/drug effects , Colon/microbiology , Colon/pathology , Disease Models, Animal , Dysbiosis/microbiology , Female , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/genetics , Indoles/therapeutic use , Inflammation/prevention & control , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , RNA, Ribosomal, 16S/genetics , Th17 Cells , Interleukin-22
10.
Mol Nutr Food Res ; 64(1): e1900633, 2020 01.
Article in English | MEDLINE | ID: mdl-31730734

ABSTRACT

SCOPE: Colitis, an inflammatory bowel disease, is associated with aberrant regulation of the colonic mucosal immune system. Resveratrol, a natural plant product, has been found to exert anti-inflammatory properties and attenuate the development of murine colitis. In the current study, the role of microRNA (miR) in the ability of resveratrol to suppress colonic inflammation is examined. METHODS AND RESULTS: BALB/C mice with 2,4,6-Trinitrobenzenesulfonic acid solution (TNBS)-induced colitis, when treated with resveratrol, show improved clinical outcomes and reduce induction of inflammatory T cells (Th17 and Th1) while increasing CD4+Foxp3+ regulatory T cells (Tregs) and IL-10-producing CD4+ T cells. miR microarray analysis and polymerase chain reaction (PCR) validation from CD4+ T cells show treatment with resveratrol decreases the expression of several miRs (miR-31, Let7a, miR-132) that targets cytokines and transcription factors involved in anti-inflammatory T cell responses (Foxp3 and TGF-ß). Transfection studies with miR-31 confirm that this miR directly regulates the expression of Foxp3. Lastly, analysis of public data from human patients with ulcerative colitis reveals that miR-31 expression is significantly increased when compared to controls. CONCLUSION: Together, the current study demonstrates that resveratrol-mediated attenuation of colitis may be regulated by miR-31 through induction of Tregs and miR-31 may serve as a therapeutic target for human colitis.


Subject(s)
Colitis, Ulcerative/genetics , Colitis/prevention & control , MicroRNAs/genetics , Resveratrol/pharmacology , T-Lymphocytes, Regulatory/drug effects , Animals , Case-Control Studies , Colitis/chemically induced , Colitis/drug therapy , Colitis/genetics , Down-Regulation/drug effects , Female , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation/drug effects , Humans , Mice, Inbred C57BL , T-Lymphocytes, Regulatory/physiology , Th17 Cells/drug effects , Trinitrobenzenesulfonic Acid/toxicity
11.
Front Microbiol ; 10: 2349, 2019.
Article in English | MEDLINE | ID: mdl-31681214

ABSTRACT

The Aryl Hydrocarbon Receptor (AhR) is a transcription factor that, when activated by ligand-binding, has been shown to regulate the immune response. Pertussis Toxin (PTX) is a virulence factor found in Bordetella pertussis, a human respiratory pathogen that causes whooping cough. PTX promotes colonization and disease promotion by triggering a heightened inflammatory response. The role of AhR in the regulation of PTX-mediated inflammation has not previously been studied. In the current study, we investigate if AhR activation by 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), a well characterized ligand, can attenuate PTX-mediated systemic inflammation. To that end, C57BL/6 mice were injected intraperitoneally (IP) with PTX twice and treated with TCDD or vehicle (VEH). The PTX+VEH group showed elevated levels of pro-inflammatory cytokines (IL-17A, IL-6, and IFNγ) in serum and increased proportions of CD4+ Th1 and Th17 cells in their spleens. In contrast, the PTX+TCDD group showed significantly lower levels of these inflammatory cytokines and decreased proportions of Th1 and Th17 cells, but increased proportions of Th2 and FoxP3+Tregs when compared to the PTX+VEH group. PTX+TCDD treated mice also showed elevated levels of IL-10, and TFG-b, potent anti-inflammatory cytokines. MicroRNAs (miRs) analysis of CD4+ T cells from the spleens of the PTX+TCDD treated mice revealed significant alterations in their expression and several of these miRs targeted cytokines and signaling molecules involved in inflammation. Specifically, the PTX+TCDD group had a significantly enhanced expression of miR-3082-5p that targeted IL-17, and a decreased expression of miR-1224-5p, which targeted FoxP3. Transfection studies with these miR mimics and inhibitors confirmed the specificity of the target genes. The current study suggests that AhR activation by TCDD suppresses PTX-induced inflammation through miR regulation that triggers reciprocal polarization of Tregs and Th17 cells and also suggests that AhR activation may serve as a treatment modality to suppress heightened inflammation induced during B. pertussis infection.

12.
J Immunol ; 203(7): 1830-1844, 2019 10 01.
Article in English | MEDLINE | ID: mdl-31492743

ABSTRACT

The compound 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant, is a potent ligand for aryl hydrocarbon receptor (AhR). In the current study, we made an exciting observation that naive C57BL/6 mice that were exposed i.p. to TCDD showed massive mobilization of myeloid-derived suppressor cells (MDSCs) in the peritoneal cavity. These MDSCs were highly immunosuppressive and attenuated Con A-induced hepatitis upon adoptive transfer. TCDD administration in naive mice also led to induction of several chemokines and cytokines in the peritoneal cavity and serum (CCL2, CCL3, CCL4, CCL11, CXCL1, CXCL2, CXCL5, CXCL9, G-CSF, GM-CSF, VEGF, and M-CSF) and chemokine receptors on MDSCs (CCR1, CCR5, and CXCR2). Treatment with CXCR2 or AhR antagonist in mice led to marked reduction in TCDD-induced MDSCs. TCDD-induced MDSCs had high mitochondrial respiration and glycolytic rate and exhibited differential microRNA (miRNA) expression profile. Specifically, there was significant downregulation of miR-150-5p and miR-543-3p. These two miRNAs targeted and enhanced anti-inflammatory and MDSC-regulatory genes, including IL-10, PIM1, ARG2, STAT3, CCL11 and its receptors CCR3 and CCR5 as well as CXCR2. The role of miRs in MDSC activation was confirmed by transfection studies. Together, the current study demonstrates that activation of AhR in naive mice triggers robust mobilization of MDSCs through induction of chemokines and their receptors and MDSC activation through regulation of miRNA expression. AhR ligands include diverse compounds from environmental toxicants, such as TCDD, that are carcinogenic to dietary indoles that are anti-inflammatory. Our studies provide new insights on how such ligands may regulate health and disease through induction of MDSCs.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors/immunology , Gene Expression Regulation/immunology , Immune Tolerance , Myeloid-Derived Suppressor Cells/immunology , Receptors, Aryl Hydrocarbon/immunology , Receptors, Interleukin-8B/immunology , Animals , Basic Helix-Loop-Helix Transcription Factors/agonists , Chemokines/immunology , Female , Gene Expression Regulation/drug effects , Inflammation/chemically induced , Inflammation/immunology , Inflammation/pathology , Mice , MicroRNAs , Myeloid-Derived Suppressor Cells/pathology , Polychlorinated Dibenzodioxins/toxicity , Receptors, Aryl Hydrocarbon/agonists
13.
Brain Behav Immun ; 82: 25-35, 2019 11.
Article in English | MEDLINE | ID: mdl-31356922

ABSTRACT

Currently, a combination of marijuana cannabinoids including delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is used as a drug to treat muscle spasticity in patients with Multiple Sclerosis (MS). Because these cannabinoids can also suppress inflammation, it is unclear whether such patients benefit from suppression of neuroinflammation and if so, what is the mechanism through which cannabinoids act. In the currently study, we used a murine model of MS, experimental autoimmune encephalomyelitis (EAE), to study the role of gut microbiota in the attenuation of clinical signs of paralysis and inflammation caused by cannabinoids. THC + CBD treatment attenuated EAE and caused significant decrease in inflammatory cytokines such as IL-17 and IFN-γ while promoting the induction of anti-inflammatory cytokines such as IL-10 and TGF-ß. Use of 16S rRNA sequencing on bacterial DNA extracted from the gut revealed that EAE mice showed high abundance of mucin degrading bacterial species, such as Akkermansia muciniphila (A. muc), which was significantly reduced after THC + CBD treatment. Fecal Material Transfer (FMT) experiments confirmed that THC + CBD-mediated changes in the microbiome play a critical role in attenuating EAE. In silico computational metabolomics revealed that LPS biosynthesis, a key component in gram-negative bacteria such as A. muc, was found to be elevated in EAE mice which was confirmed by demonstrating higher levels of LPS in the brain, while treatment with THC + CBD reversed this trend. EAE mice treated with THC + CBD also had significantly higher levels of short chain fatty acids such as butyric, isovaleric, and valeric acids compared to naïve or disease controls. Collectively, our data suggest that cannabinoids may attenuate EAE and suppress neuroinflammation by preventing microbial dysbiosis seen during EAE and promoting healthy gut microbiota.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/microbiology , Gastrointestinal Microbiome/drug effects , Animals , Cannabidiol/therapeutic use , Cannabinoids/therapeutic use , Cannabis/metabolism , Cytokines/metabolism , Disease Models, Animal , Dronabinol/therapeutic use , Dysbiosis/complications , Encephalomyelitis, Autoimmune, Experimental/immunology , Female , Gastrointestinal Microbiome/physiology , Inflammation/complications , Interferon-gamma/immunology , Interleukin-17/metabolism , Mice , Mice, Inbred C57BL , Multiple Sclerosis , RNA, Ribosomal, 16S/genetics
14.
Sci Rep ; 9(1): 8742, 2019 06 19.
Article in English | MEDLINE | ID: mdl-31217465

ABSTRACT

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated with increased NOX-2, an NADPH oxidase isoform. Activationof NOX2 caused inflammasome activation as shown by NLRP3/ASCII and NLRP3/Casp-1 colocalizations in these cells while use of mice lacking a crucial NOX2 component attenuated inflammatory pathology and redox changes. Mechanistically, NOX2 mediated peroxynitrite species were primary to inflammasome activation and release of inflammatory mediators. Thus, in conclusion, microcystin exposure in NAFLD could significantly alter intestinal pathology especially by the effects on microbiome and resultant redox status thus advancing our understanding of the co-existence of NAFLD-linked inflammatory bowel disease phenotypes in the clinic.


Subject(s)
Environmental Exposure/adverse effects , Gastrointestinal Microbiome/drug effects , Intestinal Diseases , Microcystins/administration & dosage , NADPH Oxidase 2/metabolism , Non-alcoholic Fatty Liver Disease , Animals , Disease Models, Animal , Inflammation/chemically induced , Inflammation/enzymology , Inflammation/microbiology , Inflammation/pathology , Intestinal Diseases/chemically induced , Intestinal Diseases/enzymology , Intestinal Diseases/microbiology , Intestinal Diseases/pathology , Male , Mice , Mice, Knockout , Microcystins/pharmacology , Non-alcoholic Fatty Liver Disease/enzymology , Non-alcoholic Fatty Liver Disease/microbiology , Non-alcoholic Fatty Liver Disease/pathology
15.
J Leukoc Biol ; 106(2): 467-480, 2019 08.
Article in English | MEDLINE | ID: mdl-30897248

ABSTRACT

Inflammatory diseases of the gastrointestinal tract are often associated with microbial dysbiosis. Thus, dietary interactions with intestinal microbiota, to maintain homeostasis, play a crucial role in regulation of clinical disorders such as colitis. In the current study, we investigated if resveratrol, a polyphenol found in a variety of foods and beverages, would reverse microbial dysbiosis induced during colitis. Administration of resveratrol attenuated colonic inflammation and clinical symptoms in the murine model of 2,4,6-trinitrobenzenesulfonic acid (TNBS)-induced colitis. Resveratrol treatment in mice with colitis led to an increase in CD4+ FOXP3+ and CD4+ IL-10+ T cells, and a decrease in CD4+ IFN-γ+ and CD4+ IL-17+ T cells. 16S rRNA gene sequencing to investigate alterations in the gut microbiota revealed that TNBS caused significant dysbiosis, which was reversed following resveratrol treatment. Analysis of cecal flush revealed that TNBS administration led to an increase in species such as Bacteroides acidifaciens, but decrease in species such as Ruminococcus gnavus and Akkermansia mucinphilia, as well as a decrease in SCFA i-butyric acid. However, resveratrol treatment restored the gut bacteria back to homeostatic levels, and increased production of i-butyric acid. Fecal transfer experiments confirmed the protective role of resveratrol-induced microbiota against colitis inasmuch as such recipient mice were more resistant to TNBS-colitis and exhibited polarization toward CD4+ FOXP3+ T cells and decreases in CD4+ IFN-γ+ and CD4+ IL-17+ T cells. Collectively, these data demonstrate that resveratrol-mediated attenuation of colitis results from reversal of microbial dysbiosis induced during colitis and such microbiota protect the host from colonic inflammation by inducing Tregs while suppressing inflammatory Th1/Th17 cells.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Colitis/etiology , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Immunomodulation/drug effects , Resveratrol/pharmacology , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Animals , Biomarkers , Colitis/metabolism , Colitis/pathology , Colitis/prevention & control , Colonoscopy , Disease Models, Animal , Fecal Microbiota Transplantation , Female , Humans , Metagenomics/methods , Mice , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , T-Lymphocytes, Regulatory/drug effects , T-Lymphocytes, Regulatory/metabolism , Th17 Cells/drug effects , Th17 Cells/metabolism
16.
J Cell Mol Med ; 22(5): 2644-2655, 2018 05.
Article in English | MEDLINE | ID: mdl-29512867

ABSTRACT

Staphylococcal enterotoxin B (SEB) is a potent superantigen produced by Staphylococcus aureus that triggers a strong immune response, characterized by cytokine storm, multi-organ failure, and often death. When inhaled, SEB can cause acute lung injury (ALI) and respiratory failure. In this study, we investigated the effect of resveratrol (RES), a phytoallexin, on SEB-driven ALI and mortality in mice. We used a dual-exposure model of SEB in C3H/HeJ mice, which caused 100% mortality within the first 5 days of exposure, and treatment with RES resulted in 100% survival of these mice up to 10 days post-SEB exposure. RES reduced the inflammatory cytokines in the serum and lungs, as well as T cell infiltration into the lungs caused by SEB. Treatment with RES also caused increased production of transforming growth factor-beta (TGF-ß) in the blood and lungs. RES altered the miRNA profile in the immune cells isolated from the lungs. Of these, miR-193a was strongly induced by SEB and was down-regulated by RES treatment. Furthermore, transfection studies and pathway analyses revealed that miR-193a targeted several molecules involved in TGF-ß signalling (TGFß2, TGFßR3) and activation of apoptotic pathways death receptor-6 (DR6). Together, our studies suggest that RES can effectively neutralize SEB-mediated lung injury and mortality through potential regulation of miRNA that promote anti-inflammatory activities.


Subject(s)
Acute Lung Injury/drug therapy , Acute Lung Injury/genetics , MicroRNAs/metabolism , Protective Agents/therapeutic use , Resveratrol/therapeutic use , Signal Transduction , Transforming Growth Factor beta/metabolism , Acute Lung Injury/chemically induced , Animals , Base Sequence , Bronchoalveolar Lavage Fluid , Cytokines/blood , Cytokines/metabolism , Down-Regulation/drug effects , Enterotoxins , Female , Lung/pathology , Mice , Mice, Inbred C3H , MicroRNAs/genetics , Protective Agents/pharmacology , Resveratrol/pharmacology
17.
PLoS One ; 10(2): e0118506, 2015.
Article in English | MEDLINE | ID: mdl-25706292

ABSTRACT

Staphylococcal enterotoxin B (SEB) is a potent superantigen capable of inducing inflammation characterized by robust immune cell activation and proinflammatory cytokine release. Exposure to SEB can result in food poisoning as well as fatal conditions such as toxic shock syndrome. In the current study, we investigated the effect of natural indoles including indole-3-carbinol (I3C) and 3,3'-diindolylmethane (DIM) on SEB-mediated liver injury. Injection of SEB into D-galactosamine-sensitized female C57BL/6 mice resulted in liver injury as indicated by an increase in enzyme aspartate transaminase (AST) levels, induction of inflammatory cytokines, and massive infiltration of immune cells into the liver. Administration of I3C and DIM (40 mg/kg), by intraperitonal injection, attenuated SEB-induced acute liver injury, as evidenced by decrease in AST levels, inflammatory cytokines and cellular infiltration in the liver. I3C and DIM triggered apoptosis in SEB-activated T cells primarily through activation of the intrinsic mitochondrial pathway. In addition, inhibitor studies involving caspases revealed that I3C and DIM-mediated apoptosis in these activated cells was dependent on caspase-2 but independent of caspase-8, 9 and 3. In addition, I3C and DIM caused a decrease in Bcl-2 expression. Both compounds also down-regulated miR-31, which directly targets caspase-2 and influences apoptosis in SEB-activated cells. Our data demonstrate for the first time that indoles can effectively suppress acute hepatic inflammation caused by SEB and that this may be mediated by decreased expression of miR-31 and consequent caspase-2-dependent apoptosis in T cells.


Subject(s)
Apoptosis/drug effects , Caspase 2/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Indoles/pharmacology , MicroRNAs/genetics , Animals , Apoptosis/genetics , Aspartate Aminotransferases/metabolism , Blotting, Western , Caspase 2/genetics , Chemical and Drug Induced Liver Injury/genetics , Chemical and Drug Induced Liver Injury/metabolism , Cytokines/metabolism , Down-Regulation/drug effects , Enterotoxins/immunology , Enterotoxins/toxicity , Female , Inflammation Mediators/metabolism , Liver/drug effects , Liver/immunology , Liver/metabolism , Mice, Inbred C57BL , Proto-Oncogene Proteins c-bcl-2/genetics , Proto-Oncogene Proteins c-bcl-2/metabolism , Reverse Transcriptase Polymerase Chain Reaction , T-Lymphocytes/drug effects , T-Lymphocytes/metabolism
18.
Toxicol Appl Pharmacol ; 274(1): 7-16, 2014 Jan 01.
Article in English | MEDLINE | ID: mdl-24200994

ABSTRACT

Staphylococcal enterotoxin B (SEB) is a potent exotoxin produced by the Staphylococcus aureus. This toxin is classified as a superantigen because of its ability to directly bind with MHC-II class molecules followed by activation of a large proportion of T cells bearing specific Vß-T cell receptors. Commonly associated with classic food poisoning, SEB has also been shown to induce toxic shock syndrome, and is also considered to be a potential biological warfare agent because it is easily aerosolized. In the present study, we assessed the ability of indole-3-carbinol (I3C) and one of its byproducts, 3,3'-diindolylmethane (DIM), found in cruciferous vegetables, to counteract the effects of SEB-induced activation of T cells in mice. Both I3C and DIM were found to decrease the activation, proliferation, and cytokine production by SEB-activated Vß8(+) T cells in vitro and in vivo. Interestingly, inhibitors of histone deacetylase class I (HDAC-I), but not class II (HDAC-II), showed significant decrease in SEB-induced T cell activation and cytokine production, thereby suggesting that epigenetic modulation plays a critical role in the regulation of SEB-induced inflammation. In addition, I3C and DIM caused a decrease in HDAC-I but not HDAC-II in SEB-activated T cells, thereby suggesting that I3C and DIM may inhibit SEB-mediated T cell activation by acting as HDAC-I inhibitors. These studies not only suggest for the first time that plant-derived indoles are potent suppressors of SEB-induced T cell activation and cytokine storm but also that they may mediate these effects by acting as HDAC inhibitors.


Subject(s)
Epigenesis, Genetic/drug effects , Histone Deacetylase 1/antagonists & inhibitors , Histone Deacetylase Inhibitors/pharmacology , Indoles/pharmacology , T-Lymphocytes/drug effects , Animals , Enterotoxins/antagonists & inhibitors , Enterotoxins/toxicity , Epigenesis, Genetic/physiology , Female , Gene Expression Regulation, Enzymologic , Histone Deacetylase 1/metabolism , Histone Deacetylase Inhibitors/chemistry , Indoles/chemistry , Mice , Mice, Inbred C57BL , T-Lymphocytes/metabolism
19.
Nutr Rev ; 71(6): 353-69, 2013 Jun.
Article in English | MEDLINE | ID: mdl-23731446

ABSTRACT

The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3(+) regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases.


Subject(s)
Immunomodulation/immunology , Receptors, Aryl Hydrocarbon/immunology , Receptors, Aryl Hydrocarbon/physiology , Cell Differentiation , Humans , Immunomodulation/physiology , Inflammation/immunology , Signal Transduction/immunology , T-Lymphocytes/cytology , T-Lymphocytes/immunology
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