Nrf2 Is a Protective Factor against Oxidative Stresses Induced by Diesel Exhaust Particle in Allergic Asthma

Epidemiological studies have shown that air pollutants, such as diesel exhaust particle (DEP), are implicated in the increased incidence of allergic airway disorders.In vitrostudies of molecular mechanisms have focused on the role of reactive oxygen species generated directly and indirectly by the exposure to DEP. Antioxidants effectively reduce the allergic inflammatory effects induced by DEP bothin vitroandin vivo. On the other hand, Nrf2 is a transcription factor essential for the inducible and/or constitutive expression of phase II and antioxidant enzymes. Disruption ofNrf2enhances susceptibility to airway inflammatory responses and exacerbation of allergic inflammation induced by DEP in mice. Host responses to DEP are regulated by a balance between antioxidants and proinflammatory responses. Nrf2 may be an important protective factor against oxidative stresses induced by DEP in airway inflammation and allergic asthma and is expected to contribute to chemoprevention against DEP health effects in susceptible individuals.

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Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

Toxicological Sciences ◽

10.1093/toxsci/kfaa022 ◽

2020 ◽

Vol 175 (1) ◽

pp. 64-74 ◽

Cited By ~ 3

Author(s):

Nivedita Banerjee ◽

Hui Wang ◽

Gangduo Wang ◽

M Firoze Khan

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Autoimmune Response ◽

Mediated Effects ◽

Antioxidant Gene Expression ◽

Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

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USP38 critically promotes asthmatic pathogenesis by stabilizing JunB protein

Journal of Experimental Medicine ◽

10.1084/jem.20172026 ◽

2018 ◽

Vol 215 (11) ◽

pp. 2850-2867 ◽

Cited By ~ 4

Author(s):

Siyuan Chen ◽

Fenglin Yun ◽

Yikun Yao ◽

Mengtao Cao ◽

Yifan Zhang ◽

...

Keyword(s):

Allergic Asthma ◽

Molecular Mechanisms ◽

Protein Stabilization ◽

Th2 Immune Response ◽

Specific Protease ◽

Ubiquitin Specific Protease ◽

Th2 Immunity ◽

Th2 Development

Th2 immune response is critical for allergic asthma pathogenesis. Molecular mechanisms for regulating Th2 immunity are still not well understood. Here we report that the ubiquitin-specific protease USP38 is crucial for Th2-mediated allergic asthma. TCR stimulation up-regulated the USP38 level, and USP38 in turn mediated the protein stabilization of JunB, a transcription factor specific for Th2 development. Consequently, USP38 was specifically required for TCR-induced production of Th2 cytokines and Th2 development both in vitro and in vivo, and USP38-deficient mice were resistant to asthma pathogenesis induced by OVA or HDM. Mechanistically, USP38 directly associated with JunB, deubiquitinated Lys-48–linked poly-ubiquitination of JunB, and consequently blocked TCR-induced JunB turnover. USP38 represents the first identified deubiquitinase specifically for Th2 immunity and the associated asthma.

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Novel insights into the regulation of chemerin expression: role of acute-phase cytokines and DNA methylation

10.1101/765834 ◽

2019 ◽

Author(s):

Kamila Kwiecien ◽

Piotr Brzoza ◽

Pawel Majewski ◽

Izabella Skulimowska ◽

Kamil Bednarczyk ◽

...

Keyword(s):

Dna Methylation ◽

Acute Phase ◽

Molecular Mechanisms ◽

Retinoic Acid Receptor ◽

Constitutive Expression ◽

Sequencing Analysis ◽

Mrna Levels ◽

Pleiotropic Actions

AbstractChemerin is a chemoattractant protein with adipokine properties encoded by the retinoic acid receptor responder 2 (RARRES2) gene. It has gained more attention over the past few years due to its multilevel impact on metabolism and immune responses. The pleiotropic actions of chemerin include chemotaxis of dendritic cells, macrophages and natural killers (NK) subsets, bactericidal activity as well as regulation of adipogenesis and glucose metabolism. Therefore, reflecting the pleiotropic actions of chemerin, expression of RARRES2 is regulated by a variety of inflammatory and metabolic mediators. However, for most cell types, the molecular mechanisms controlling constitutive and regulated chemerin expression are poorly characterized. Here we show that RARRES2 mRNA levels in murine adipocytes are upregulated in vitro and in vivo by acute-phase cytokines, IL-1β and OSM. In contrast to adipocytes, these cytokines exerted a weak, if any, response in mouse hepatocytes, suggesting that the effect of IL-1β and OSM on chemerin expression is specific to fat tissue. Moreover, we show that DNA methylation controls the constitutive expression of chemerin. Bisulfite sequencing analysis showed low methylation levels within −735 to +258 bp of the murine RARRES2 gene promoter in unstimulated adipocytes and hepatocytes. In contrast to these cells, the RARRES2 promoter is highly methylated in B lymphocytes, cells that do not produce chemerin. Together, our findings reveal previously uncharacterized mediators and mechanisms controlling chemerin expression in various cells.

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IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses

eLife ◽

10.7554/elife.46836 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Rachel A Gottschalk ◽

Michael G Dorrington ◽

Bhaskar Dutta ◽

Kathleen S Krauss ◽

Andrew J Martins ◽

...

Keyword(s):

Negative Feedback ◽

Molecular Mechanisms ◽

Cytokine Production ◽

Inflammatory Responses ◽

Type I ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative

Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics.

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Dental Pulp Defence and Repair Mechanisms in Dental Caries

Mediators of Inflammation ◽

10.1155/2015/230251 ◽

2015 ◽

Vol 2015 ◽

pp. 1-16 ◽

Cited By ~ 100

Author(s):

Jean-Christophe Farges ◽

Brigitte Alliot-Licht ◽

Emmanuelle Renard ◽

Maxime Ducret ◽

Alexis Gaudin ◽

...

Keyword(s):

Dental Caries ◽

Dental Pulp ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Oral Bacteria ◽

Barrier Formation ◽

Reparative Dentin ◽

Pulp Inflammation

Dental caries is a chronic infectious disease resulting from the penetration of oral bacteria into the enamel and dentin. Microorganisms subsequently trigger inflammatory responses in the dental pulp. These events can lead to pulp healing if the infection is not too severe following the removal of diseased enamel and dentin tissues and clinical restoration of the tooth. However, chronic inflammation often persists in the pulp despite treatment, inducing permanent loss of normal tissue and reducing innate repair capacities. For complete tooth healing the formation of a reactionary/reparative dentin barrier to distance and protect the pulp from infectious agents and restorative materials is required. Clinical andin vitroexperimental data clearly indicate that dentin barrier formation only occurs when pulp inflammation and infection are minimised, thus enabling reestablishment of tissue homeostasis and health. Therefore, promoting the resolution of pulp inflammation may provide a valuable therapeutic opportunity to ensure the sustainability of dental treatments. This paper focusses on key cellular and molecular mechanisms involved in pulp responses to bacteria and in the pulpal transition between caries-induced inflammation and dentinogenic-based repair. We report, using selected examples, different strategies potentially used by odontoblasts and specialized immune cells to combat dentin-invading bacteriain vivo.

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Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

The Scientific World JOURNAL ◽

10.1100/tsw.2011.22 ◽

2011 ◽

Vol 11 ◽

pp. 320-339 ◽

Cited By ~ 74

Author(s):

Gillian R. Milne ◽

Timothy M. Palmer

Keyword(s):

Molecular Mechanisms ◽

Immune Cell ◽

Inflammatory Responses ◽

Current Evidence ◽

Receptor Subtypes ◽

Protective Effects ◽

Stress Injury ◽

Anti Inflammatory

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2Aadenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerousin vitrostudies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings fromin vivostudies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

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Diesel exhaust particulate-induced activation of Stat3 requires activities of EGFR and Src in airway epithelial cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00204.2006 ◽

2007 ◽

Vol 292 (2) ◽

pp. L422-L429 ◽

Cited By ~ 35

Author(s):

Dongsun Cao ◽

Tamara L. Tal ◽

Lee M. Graves ◽

Ian Gilmour ◽

William Linak ◽

...

Keyword(s):

Growth Factor ◽

Diesel Exhaust ◽

Inflammatory Responses ◽

Critical Role ◽

Airway Epithelial Cells ◽

Diesel Exhaust Particles ◽

Diesel Exhaust Particulate ◽

Stat3 Phosphorylation

In vivo exposure to diesel exhaust particles (DEP) elicits acute inflammatory responses in the lung characterized by inflammatory cell influx and elevated expression of mediators such as cytokines and chemokines. Signal transducers and activators of transcription (STAT) proteins are a family of cytoplasmic transcription factors that are key transducers of signaling in response to cytokine and growth factor stimulation. One member of the STAT family, Stat3, has been implicated as a regulator of inflammation but has not been studied in regard to DEP exposure. The results of this study show that DEP induces Stat3 phosphorylation as early as 1 h following stimulation and that phosphorylated Stat3 translocates into the nucleus. Inhibition of epidermal growth factor receptor (EGFR) and Src activities by the inhibitors PD-153035 and PP2, respectively, abolished the activation of Stat3 by DEP, suggesting that Stat3 activation by DEP requires EGFR and Src kinase activation. The present study suggests that oxidative stress induced by DEP may play a critical role in activating EGFR signaling, as evidenced by the fact that pretreatment with antioxidant prevented the activation of EGFR and Stat3. These findings demonstrate that DEP inhalation can activate proinflammatory Stat3 signaling in vitro.

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Notch1 signaling stimulates proliferation of immature cardiomyocytes

The Journal of Cell Biology ◽

10.1083/jcb.200806091 ◽

2008 ◽

Vol 183 (1) ◽

pp. 117-128 ◽

Cited By ~ 112

Author(s):

Chiara Collesi ◽

Lorena Zentilin ◽

Gianfranco Sinagra ◽

Mauro Giacca

Keyword(s):

Notch Signaling ◽

Cardiac Myocytes ◽

Molecular Mechanisms ◽

Notch Pathway ◽

Constitutive Expression ◽

Neonatal Rat ◽

Proliferative Potential ◽

Rat Cardiomyocytes

The identification of the molecular mechanisms controlling cardiomyocyte proliferation during the embryonic, fetal, and early neonatal life appears of paramount interest in regard to exploiting this information to promote cardiac regeneration. Here, we show that the proliferative potential of neonatal rat cardiomyocytes is powerfully stimulated by the sustained activation of the Notch pathway. We found that Notch1 is expressed in proliferating ventricular immature cardiac myocytes (ICMs) both in vitro and in vivo, and that the number of Notch1-positive cells in the heart declines with age. Notch1 expression in ICMs paralleled the expression of its Jagged1 ligand on non-myocyte supporting cells. The inhibition of Notch signaling in ICMs blocked their proliferation and induced apoptosis; in contrast, its activation by Jagged1 or by the constitutive expression of its activated form using an adeno-associated virus markedly stimulated proliferative signaling and promoted ICM expansion. Maintenance or reactivation of Notch signaling in cardiac myocytes might represent an interesting target for innovative regenerative therapy.

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Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

10.21203/rs.3.rs-19583/v1 ◽

2020 ◽

Author(s):

Han Seok Koh ◽

Hannah Jang ◽

SooKil Tae ◽

mi-sun Lee ◽

Jae-Woong Min ◽

...

Keyword(s):

Mouse Model ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Amyloid Β ◽

Neuronal Loss ◽

Precentral Gyrus ◽

Alzheimer Patient ◽

5Xfad Mice

Abstract Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Aβ processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Aβ processing and clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Result This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

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Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1

Molecules ◽

10.3390/molecules26196073 ◽

2021 ◽

Vol 26 (19) ◽

pp. 6073

Author(s):

Laily Rahmawati ◽

Nur Aziz ◽

Jieun Oh ◽

Yo Han Hong ◽

Byoung Young Woo ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Models ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Raw264.7 Cells ◽

Acute Gastritis ◽

Anti Inflammatory

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE2, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1.

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