Immunotoxicology: Modulation of the Immune System by Xenobiotics

Starting wih a definition of immunity, this review describes general mechanisms by which immune system is modulated and details several immunotoxicological screening methods to assess the immumologic and host resistance alterations following chemical exposure. Among a variety of immuno toxic compounds known, only four representative compounds namely o-chloro benzylidine malononitrile (CS), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), chloroquine, 1,3 bis (2-chloroethyl) 1-nitrosourea (BCNU) have been chosen for an elaborate discussion

Cannabidiol Attenuates Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis Through Induction of Myeloid-Derived Suppressor Cells

Multiple sclerosis (MS) is a chronic debilitating autoimmune disease without a cure. While the use of marijuana cannabinoids for MS has recently been approved in some countries, the precise mechanism of action leading to attenuate neuroinflammation is not clear. We used experimental autoimmune encephalomyelitis (EAE), a murine model of MS, to explore the anti-inflammatory properties of cannabidiol (CBD), a non-psychoactive cannabinoid. Treatment with CBD caused attenuation of EAE disease paradigms as indicated by a significant reduction in clinical scores of paralysis, decreased T cell infiltration in the central nervous system, and reduced levels of IL-17 and IFNγ. Interestingly, CBD treatment led to a profound increase in myeloid-derived suppressor cells (MDSCs) in EAE mice when compared to the vehicle-treated EAE controls. These MDSCs caused robust inhibition of MOG-induced proliferation of T cells in vitro. Moreover, adoptive transfer of CBD-induced MDSCs ameliorated EAE while MDSC depletion reversed the beneficial effects of CBD treatment, thereby conclusively demonstrating that MDSCs played a crucial role in CBD-mediated attenuation of EAE. Together, these studies demonstrate for the first time that CBD treatment may ameliorate EAE through induction of immunosuppressive MDSCs

Cannabinoid Receptor 1 Blockade Attenuates Obesity and Adipose Tissue Type 1 Inflammation Through miR-30e-5p Regulation of Delta-Like-4 in Macrophages and Consequently Downregulation of Th1 Cells

Obesity is characterized by chronic low-grade inflammation that contributes to development of cardiometabolic disorders. Cannabinoid receptor 1 (CB1) antagonists attenuate diet-induced obesity (DIO) and related inflammation, although the precise anti-inflammatory mechanisms involved have not been fully explored. In the current study we used a mouse model of DIO intervention to determine the microRNA (miRNA, miR)-mediated anti-obesity and anti-inflammatory effects of the CB1 antagonist, AM251. DIO mice that were fed high-fat diet (HFD) for 12 weeks were treated with AM251 (10 mg/kg) for an additional 4 weeks. HFD + AM251 mice experienced rapid and prolonged weight loss and reduced inflammatory M1 adipose tissue macrophage (ATM) infiltration. To investigate miRNA-mediated regulation of ATMs, F4/80+ cells from stromal vascular fractions (SVF) of epididymal fat were subjected to miR microarray analysis. Several miRs were differentially expressed in AM251-treated mice that were independent of calorie restriction. Prominently, miR-30e-5p was upregulated in ATMs from HFD + AM251 mice while the miR-30e-5p target, DLL4, was downregulated. Consistent with a decrease in DLL4-Notch signaling, fat storage and pro-inflammatory cytokine/chemokine expression was reduced following AM251 treatment. Furthermore, we found that AM251-treated macrophages can suppress DLL4-mediated Th1 polarization in CD4+ T cells. Together these data demonstrate that blocking CB1 receptors leads to upregulation of miR-30e-5p and down regulation of DLL4 in ATMs, which in turn suppress DLL4-Notch signaling-induced polarization of inflammatory Th1 cells and adipocyte energy storage. This combined effect of ATMs and T cells leads to an anti-inflammatory state and attenuation of DIO. These data support therapeutic potential of miR-30 in the treatment of cardiometabolic disorders

Deficiency of KLF4 Compromises the Lung Function in an Acute Mouse Model of Allergic Asthma

Asthma is a chronic inflammatory disease of the airways and the mechanisms are not fully understood. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of monocytes, granulocyte and myeloid cells at early stage of differentiation. They possess phenotypic plasticity and regulate airway inflammation. We recently reported that Kruppel-like factor 4 (KLF4) regulates MDSC differentiation into fibrocytes, emerging effectors in chronic inflammation. However, the role of KLF4 in asthma is not known. Thymic stromal lymphopoietin (TSLP) is an epithelial cell-derived cytokine and a key initiator of allergic airway inflammation. Given the fact that TSLP promotes Th2 cytokine production that increases MDSC differentiation into fibrocytes, we postulate that KLF4 regulates asthma in a TSLP-dependent manner. In this study, we utilized a model of allergic asthma with ovalbumin challenge (OVA). We found that upon OVA treatment the wild type mice had increased MDSC infiltration into the lung, up-regulation of KLF4 and TSLP gene expression, and higher levels of Th2 cytokines including IL4 and IL13. Consistently, lack of KLF4 expression in monocytes and lung epithelial cells resulted in decreased TSLP expression and lower levels of Th2 cytokines in mice, and fibrocyte generation was compromised. KLF4 deficiency in these cells also led to decreased airway hyperresponsiveness (AHR), a cardinal feature of asthma, as assessed by whole body plethysmography. Moreover, lung fibrosis as measured by trichome staining was attenuated and the population of CD45+COL1A1+ fibrocytes was diminished in this setting. Together, our results suggest that KLF4 regulates asthma development in a TSLP- and fibrocyte-dependent manner

Surgical removal of endometriotic lesions alters local and systemic proinflammatory cytokines in endometriosis patients

To determine the impact of endometriotic lesion removal on local and systemic inflammation

Resveratrol (trans-3,5,4Ј-Trihydroxystilbene) Ameliorates Experimental Allergic Encephalomyelitis, Primarily via Induction of Apoptosis in T Cells Involving Activation of Aryl Hydrocarbon Receptor and Estrogen Receptor

ABSTRACT Resveratrol (trans-3,5,4Ј-trihydroxystilbene), a polyphenolic compound found in plant products, including red grapes, exhibits anticancer, antioxidant, and anti-inflammatory properties

Resveratrol Attenuates Allergic Asthma and Associated Inflammation in the Lungs Through Regulation of miRNA-34a That Targets FoxP3 in Mice

Asthma is a chronic inflammatory disease of airways mediated by T-helper 2 (Th2) cells involving complex signaling pathways. Although resveratrol has previously been shown to attenuate allergic asthma, the role of miRNA in this process has not been studied. We investigated the effect of resveratrol on ovalbumin-induced experimental allergic asthma in mice. To that end, BALB/c mice were immunized with ovalbumin (OVA) intraperitoneally followed by oral gavage of vehicle (OVA-veh) or resveratrol (100 mg/kg body) (OVA-res). On day 7, the experimental groups received intranasal challenge of OVA followed by 7 days of additional oral gavage of vehicle or resveratrol. At day 15, all mice were euthanized and bronchioalveolar fluid (BALF), serum and lung infiltrating cells were collected and analyzed. The data showed that resveratrol significantly reduced IL-5, IL-13, and TGF-β in the serum and BALF in mice with OVA-induced asthma. Also, we saw a decrease in CD3+CD4+, CD3+CD8+, and CD4+IL-4+ cells with increase in CD4+CD25+FOXP3+ cells in pulmonary inflammatory cell infiltrate in OVA-res group when compared to OVA-veh. miRNA expression arrays using lung infiltrating cells showed that resveratrol caused significant alterations in miRNA expression, specifically downregulating the expression of miR-34a. Additionally, miR-34a was found to target , as evidenced by enhanced expression of in the lung tissue. Also, transfection studies showed that miR-34a inhibitor upregulated expression while miR-34a-mimic downregulated expression. The current study suggests that resveratrol attenuates allergic asthma by downregulating miR-34a that induces increased expression of , a master regulator of Treg development and functions

Resveratrol-Mediated Attenuation of Staphylococcus aureus Enterotoxin B-Induced Acute Liver Injury Is Associated With Regulation of microRNA and Induction of Myeloid-Derived Suppressor Cells

Resveratrol (RES) is a polyphenolic compound found abundantly in plant products including red grapes, peanuts, and mulberries. Because of potent anti-inflammatory properties of RES, we investigated whether RES can protect from Staphylococcal enterotoxin B (SEB)-induced acute liver injury in mice. SEB is a potent super antigen that induces robust inflammation and releases inflammatory cytokines that can be fatal. We observed that SEB caused acute liver injury in mice with increases in enzyme aspartate transaminase (AST) levels, and massive infiltration of immune cells into the liver. Treatment with RES (100 mg/kg body weight) attenuated SEB-induced acute liver injury, as indicated by decreased AST levels and cellular infiltration in the liver. Interestingly, RES treatment increased the number of myeloid derived suppressor cells (MDSCs) in the liver. RES treatment led to alterations in the microRNA (miR) profile in liver mononuclear cells (MNCs) of mice exposed to SEB, and pathway analysis indicated these miRs targeted many inflammatory pathways. Of these, we identified miR-185, which was down-regulated by RES, to specifically target Colony Stimulating Factor (CSF1) using transfection studies. Moreover, the levels of CSF1 were significantly increased in RES-treated SEB mice. Because CSF1 is critical in MDSC induction, our studies suggest that RES may induce MDSCs by down-regulating miR-185 leading to increase the expression of CSF1. The data presented demonstrate for the first time that RES can effectively attenuates SEB-induced acute liver injury and that this may result from its action on miRs and induction of MDSCs