STAT1 drives M1 microglia activation and neuroinflammation under hypoxia

Butturini, Elena; Boriero, Diana; Prati, Alessandra Carcereri de; Mariotto, Sofia

doi:10.1016/j.abb.2019.05.011

Cited by 122 publications

(98 citation statements)

References 55 publications

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“…STAT1-STAT6 exist in the cytoplasm and serve an important role in the regulation of inflammatory responses. In hypoxia-activated BV2 microglia, the phosphorylation levels of STAT1 were significantly increased, which was accompanied by increased expression levels of M1 microglia markers, such as cluster of differentiation 68 and iNOS (70); however, the expression levels of these markers were significantly decreased in STAT1 -/-BV2 cells following hypoxia. Several previous studies have also identified that STaT3 is also associated with the regulation of M1 microglia polarization in both an Mcao-induced and a bilateral common carotid arteries stenosis (BcaS)-induced model of ischemic stroke (19,(71)(72)(73).…”

Section: Nf-κbmentioning

confidence: 91%

“…receptors are proteins, usually cell surface receptors, that recognize and bind to ligands and serve an important role in the signaling pathways involved in inducing local inflammation, the recruitment of new effector cells, the containment of local infection and the initiation of an adaptive immune response. Previous studies have identified that 3 important membrane receptors, Tlr4, sphingosine 1 phosphate receptors (S1PRs) and thromboxane A2 receptor (TXa2r), are closely associated with microglia polarization (31,70,79,80).…”

Section: Nrfmentioning

confidence: 99%

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Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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ischemic stroke is one of the leading causes of mortality and disability worldwide. However, there is a current lack of effective therapies available. as the resident macrophages of the brain, microglia can monitor the microenvironment and initiate immune responses. in response to various brain injuries, such as ischemic stroke, microglia are activated and polarized into the proinflammatory M1 phenotype or the anti-inflammatory M2 phenotype. The immunomodulatory molecules, such as cytokines and chemokines, generated by these microglia are closely associated with secondary brain damage or repair, respectively, following ischemic stroke. it has been shown that M1 microglia promote secondary brain damage, whilst M2 microglia facilitate recovery following stroke. in addition, autophagy is also reportedly involved in the pathology of ischemic stroke through regulating the activation and function of microglia. Therefore, this review aimed to provide a comprehensive overview of microglia activation, their functions and changes, and the modulators of these processes, including transcription factors, membrane receptors, ion channel proteins and genes, in ischemic stroke. The effects of autophagy on microglia polarization in ischemic stroke were also reviewed. Finally, future research areas of ischemic stroke and the implications of the current knowledge for the development of novel therapeutics for ischemic stroke were identified. Contents 1. introduction 2. Microglia 3. Modulatory mechanisms of microglia polarization 4. autophagy 5. conclusions

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Section: Nf-κbmentioning

confidence: 91%

Section: Nrfmentioning

confidence: 99%

Modulators of microglia activation and polarization in ischemic stroke (Review)

et al. 2020

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“…We specifically identified upstream regulators of these pathways. Significantly, all of the top shared regulators are modulators of inflammatory response: PPARγ(77), NFKB1(78), RELA(78), STAT1 (79), and SP1 (80) ( Figure 5d). Notably, we also uncovered strong signal corresponding to pathways related to ECM regulation and organization ( Figure 5d).…”

Section: Increased Connectivity Of Neuroinflammatory and Ecm Signalinmentioning

confidence: 99%

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Seney

Moon-Kim

Glausier

et al. 2020

Preprint

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Prevalence rates of opioid use disorder (OUD) have increased dramatically, accompanied by a surge of overdose deaths. While opioid dependence has been extensively studied in preclinical models, we still have a very limited understanding of the biological changes that occur in the brains of people who chronically use opioids and who are diagnosed with OUD. To address this, we conducted the largest transcriptomics study to date using postmortem brains from subjects with OUD. We focused on the dorsolateral prefrontal cortex (DLPFC) and nucleus accumbens (NAc), two regions heavily implicated in OUD. We discovered a high degree of overlap in transcripts between DLPFC and NAc in OUD, primarily associated with neuroinflammation. Moreover, additional transcripts were enriched for factors that control pro-inflammatory cytokine-mediated signaling and remodeling of the extracellular matrix (ECM). Our results also implicate a role for microglia as a critical driver for opioid-induced neuroplasticity. Overall, our findings reveal new connections between the brain’s immune system and opioid dependence in the human brain.

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“…27 Hypoxia-induced oxidative stress causes glutathionylation of STAT1 in the brain, which abnormally activates the STAT1 signaling pathway and promotes BV2 cells to transform into proinflammatory phenotype. 28 PACAP, which induces ROS, upregulates the phosphorylation level of STAT1. 29 In MCF-7 breast cancer cell line, H 2 O 2 has been reported to enhance the glutathionylation of STAT1, and promote IFN-induced apoptosis of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

et al. 2020

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Background: Macrophage polarization affects tumor growth, metabolism, and many other tumor processes. M1 macrophages can promote antitumor immunity response. Signal transducer and activator of transcription 1 (STAT1) is one of the critical transcription factors in this process, which promotes the expression of a series of inflammatory molecules. STAT1 has been reported as a potential target of reactive oxygen species (ROS)-induced glutathionylation, while the glutathionylation of STAT1 in macrophages and its underlying regulatory mechanism remains unclear. Glutaredoxin 1 (Grx1) functions as a deglutathionylation enzyme, which regulates the activities of many proteins through reversing glutathionylation. Methods: GeneChip and RT-qPCR was first applied to test the mRNA level of Grx1 in M1 macrophages. Western blot was then used to evaluate the variations of the Grx1 protein expression in M1 macrophages. Next, immunoprecipitation was used to investigate the glutathionylated STAT1 in both wild-type and Grx1 −/− mouse macrophages. Finally, the induced alterations of STAT1 activity and function by Grx1 in M1 macrophage were examined by western blot and RT-qPCR. Results: In M1-type macrophages, the levels of Grx1 were elevated. Glutathionylation of STAT1 was negatively regulated by Grx1. Furthermore, depletion of Grx1 increased the activity of STAT1, and thereby promoted the mRNA level of C-X-C motif chemokine ligand 9 (CXCL9) during M1-type polarization of macrophages. Conclusions: Grx1 controlled deglutathionylation of STAT1, which in turn might regulate M1-type polarization of macrophages.

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STAT1 drives M1 microglia activation and neuroinflammation under hypoxia

Cited by 122 publications

References 55 publications

Modulators of microglia activation and polarization in ischemic stroke (Review)

Modulators of microglia activation and polarization in ischemic stroke (Review)

Transcriptional alterations in opioid use disorder reveal an interplay between neuroinflammation and synaptic remodeling

Glutaredoxin 1 regulates macrophage polarization through mediating glutathionylation of STAT1

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