Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses

Wang, Yiran; Zhang, Xiu-Ning; Meng, Fan-Ge; Zeng, Tao

doi:10.1080/15376516.2021.1894624

Cited by 14 publications

(9 citation statements)

References 122 publications

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“…In other systems, macrophages have been shown to play key a role in xenobiotic-induced tissue injury. 53 Environmental metabolites can drive liver impairment, colitis, neurotoxicity and lung injury through the activation and polarization of macrophages. [54][55][56][57] The extent to which macrophages and other immune cells in the CV space respond to environmental factors, as well as the role of epithelial-immune cell crosstalk, is an important area for future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Little is known about the effect of xenobiotics on immune cells in the reproductive tract. In other systems, macrophages have been shown to play key a role in xenobiotic‐induced tissue injury 53 . Environmental metabolites can drive liver impairment, colitis, neurotoxicity and lung injury through the activation and polarization of macrophages 54–57 .…”

Section: Discussionmentioning

confidence: 99%

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Xenobiotic metabolites modify immune responses of the cervicovaginal epithelium: potential mechanisms underlying barrier disruption

Gerson,

Loder,

Landau

et al. 2023

BJOG

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ObjectiveXenobiotic metabolites are exogenous biochemicals that can adversely impact reproductive health. We previously identified xenobiotics in cervicovaginal fluid during pregnancy in association with short cervix. In other organ systems, xenobiotics can modify epithelial barrier function. We hypothesise that xenobiotics dysregulate epithelial cell and macrophage immune responses as a mechanism to disrupt the cervicovaginal barrier.DesignIn vitro cell culture system.SettingLaboratory within academic institution.SampleVaginal, ectocervical and endocervical epithelial cell lines and primary macrophages.MethodsCells were treated with diethanolamine (2.5 mM), ethyl glucoside (5 mM) or tartrate (2.5 mM) for 24 h.Main outcome measuresCytokines and matrix metalloproteinases were measured in cell supernatants (n = 3 per condition). One‐way analysis of variance (ANOVA) with Dunnett's test for multiple comparisons was performed.ResultsDiethanolamine induces inflammatory cytokines, whereas ethyl glucoside and tartrate generally exert anti‐inflammatory effects across all cells. Diethanolamine increases interleukin 6 (IL‐6), IL‐8, interferon γ‐induced protein 10 kDa (IP‐10), growth‐regulated oncogene (GRO), fractalkine, matrix metalloproteinase 1 (MMP‐1), MMP‐9 and MMP‐10 (p < 0.05 for all), factors involved in acute inflammation and recruitment of monocytes, neutrophils and lymphocytes. Ethyl glucoside and tartrate decrease multiple cytokines, including RANTES and MCP‐1 (p < 0.05 for all), which serve as chemotactic factors. Vaginal cells exhibit heightened inflammatory tone compared with cervical cells and macrophages, with a greater number of differentially expressed analytes after xenobiotic exposure.ConclusionsXenobiotic metabolites present in the cervicovaginal space during pregnancy modify immune responses, unveiling potential pathways through which environmental exposures may contribute to the pathogenesis of cervical remodelling preceding preterm birth. Future work identifying xenobiotic sources and routes of exposure offers the potential to modify environmental risks to improve pregnancy outcomes.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Xenobiotic metabolites modify immune responses of the cervicovaginal epithelium: potential mechanisms underlying barrier disruption

Gerson,

Loder,

Landau

et al. 2023

BJOG

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“…In this study, we found that the mechanisms underlying the protective effects seem to be mediated by the promotion of Nrf2 nuclear translocation and upregulation of Sirt1. It has been reported that activation of Nrf2 can block the M1-stimuli induced production of proinflammatory cytokines and shift the polarization towards a M2-like phenotype [28]. Sirt1 also participated in the maintenance of microglial polarization homeostasis [29], and upregulation of Sirt1 suppressed inflammatory response, oxidative damage and improved cell viability in neurons and microglia co-culture system [30].…”

Section: Plos Onementioning

confidence: 99%

β-patchoulene alleviates cognitive dysfunction in a mouse model of sepsis associated encephalopathy by inhibition of microglia activation through Sirt1/Nrf2 signaling pathway

et al. 2023

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Background Sepsis associated encephalopathy (SAE) is a common but poorly understood complication during sepsis. Currently, there are no preventive or therapeutic agents available for this neurological disorder. The present study was designed to determine the potential protective effects of β-patchoulene (β-PAE) in a mouse model of SAE and explore the putative mechanisms underpinning the beneficial effects. Materials and methods SAE was induced in C57BL/6 mice by cecal ligation and puncture(CLP). Mice were administrated with β-PAE or saline by intra-cerebral ventricle(i.c.v) injection immediately after CLP surgery. The inhibitory avoidance tests and open field tests were performed at 24h, 48h and 7days after procedures. Cytokines expression, oxidative parameters, microglia polarization and apoptosis in the brain tissue were assessed. Sirt1, Nrf2, HO-1and cleaved-caspase3 expression in hippocampus was determined by western-blotting. Further, serum cytokines expression and spleen lymphocytes apoptosis were evaluated, and survival study was performed. Results Septic mice suffered severe cognitive decline following CLP as evidenced by decreased memory latency time and lower frequency of line crossing in the behavioral tests. A high dose of β-PAE(1mg/kg) improved the cognitive impairment in SAE mice, which was accompanied by reduced cytokines expression and oxidative stress. Immunofluorescence assay showed that β-PAE inhibited the expression of Iba-1 and iNOS in microglia. The mechanistic study indicated that β-PAE could promote the nuclear expression of Sirt1/Nrf2 and enhance cytoplasmic HO-1 expression. Furthermore, i.c.v administration of β-PAE decreased the expression of serum cytokines and apoptosis in the spleen, thus leading to an improved 7-day survival of septic mice. Finally, blockade of Nrf2 activation with ML385 largely mitigated the protective effects of β-PAE on the cognitive function, neuroinflammation and survival in SAE mice. Conclusion In this study, we found that β-PAE significantly altered sepsis induced neuroinflammation and microglia activation, thus reversed the cognitive decline and improved the peripheral immune function. The neuroprotective effects were possibly mediated by the activation of Sirt1/Nrf2/HO-1 pathway. β-PAE might serve as a promising therapeutic agent for SAE prevention and treatment.

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“…and, in the process, to polarize macrophages toward the anti-inflammatory M2 phenotype by cross-talk with NF-κB, mitogen-activated protein kinases (MAPKs), peroxisome proliferatoractivated receptor γ (PPARγ), and autophagy. Conversely, the redox independent pathway is thought to involve the direct suppressive action of Nrf2 on the genes of pro-inflammatory cytokines, preventing their transcriptional upregulation [38][39][40].…”

Section: Pneumonia and Ardsmentioning

confidence: 99%

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations

Calabrese

Kozumbo

Kapoor

et al. 2021

Radiotherapy and Oncology

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Novel mechanistic insights are discussed herein that link a single, nontoxic, low-dose radiotherapy (LDRT) treatment (0.5-1.0 Gy) to (1) beneficial subcellular effects mediated by the activation of nuclear factor erythroid 2-related transcription factor (Nrf2) and to (2) favorable clinical outcomes for COVID-19 pneumonia patients displaying symptoms of acute respiratory distress syndrome (ARDS). We posit that the favorable clinical outcomes following LDRT result from potent Nrf2-mediated antioxidant responses that rebalance the oxidatively skewed redox states of immunological cells, driving them toward anti-inflammatory phenotypes. Activation of Nrf2 by ionizing radiation is highly dose dependent and conforms to the features of a biphasic (hormetic) dose-response. At the cellular and subcellular levels, hormetic doses of < 1.0 Gy induce polarization shifts in the predominant population of lung macrophages, from an M1 pro-inflammatory to an M2 anti-inflammatory phenotype. Together, the Nrf2-mediated antioxidant responses and the subsequent shifts to anti-inflammatory phenotypes have the capacity to suppress cytokine storms, resolve inflammation, promote tissue repair, and prevent COVID-19-related mortality. Given these mechanistic considerations—and the historical clinical success of LDRT early in the 20 th century—we opine that LDRT should be regarded as safe and effective for use at almost any stage of COVID-19 infection. In theory, however, optimal life-saving potential is thought to occur when LDRT is applied prior to the cytokine storms and before the patients are placed on mechanical oxygen ventilators. The administration of LDRT either as an intervention of last resort or too early in the disease progression may be far less effective in saving the lives of ARDS patients.

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Targeting macrophage polarization by Nrf2 agonists for treating various xenobiotics-induced toxic responses

Cited by 14 publications

References 122 publications

Xenobiotic metabolites modify immune responses of the cervicovaginal epithelium: potential mechanisms underlying barrier disruption

Xenobiotic metabolites modify immune responses of the cervicovaginal epithelium: potential mechanisms underlying barrier disruption

β-patchoulene alleviates cognitive dysfunction in a mouse model of sepsis associated encephalopathy by inhibition of microglia activation through Sirt1/Nrf2 signaling pathway

Nrf2 activation putatively mediates clinical benefits of low-dose radiotherapy in COVID-19 pneumonia and acute respiratory distress syndrome (ARDS): Novel mechanistic considerations

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