Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia

Johann, Sonja; Beyer, Cordian

doi:10.1016/j.jsbmb.2012.11.006

Cited by 95 publications

(71 citation statements)

References 159 publications

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“…It is generally assumed and documented that astroglia and microglia function is positively correlated with beneficial steroid effects, and that such hormone-glia interactions ameliorate hypoxia-related brain damage [55,56,57,58,59,60]. For instance, E2 stimulates the shift of microglia from a destructive M1 into a protective M2 phenotype similar to T-cell regulation [61].…”

Section: Discussionmentioning

confidence: 99%

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

et al. 2015

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CNS ischemia results in locally confined and rapid tissue damage accompanied by a loss of neurons and their circuits. Early and time-delayed inflammatory responses are critical variables determining the extent of neural disintegration and regeneration. Inflammasomes are vital effectors in innate immunity. Their activation in brain-intrinsic immune cells contributes to ischemia-related brain damage. The steroids 17β-estradiol (E2) and progesterone (P) are neuroprotective and anti-inflammatory. Using a transient focal rat ischemic model, we evaluated the time response of different inflammasomes in the peri-infarct zone from the early to late phases after poststroke ischemia. We show that the different inflammasome complexes reveal a specific time-oriented sequential expression pattern with a maximum at approximately 24 h after the infarct. Within the limits of antibody availability, immunofluorescence labeling demonstrated that microglia and neurons are major sources of the locally activated inflammasomes NOD-like receptor protein-3 (NLRP3) and associated speck-like protein (ASC), respectively. E2 and P given for 24 h immediately after ischemia onset reduced hypoxia-induced mRNA expression of the inflammasomes NLRC4, AIM2 and ASC, and decreased the protein levels of ASC and NLRP3. In addition, mRNA protein levels of the cytokines interleukin-1β (IL1β), IL18 and TNFα were reduced by the steroids. The findings provide for the first time a detailed flow chart of hypoxia-driven inflammasome regulation in the peri-infarct cerebral cortex. Further, we demonstrate that E2 and P alleviate the expression of certain inflammasome components, sometimes in a hormone-specific way. Besides directly regulating other cellular neuroprotective pathways, the control of inflammasomes by these steroids might contribute to its neuroprotective potency.

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Section: Discussionmentioning

confidence: 99%

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

et al. 2015

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“…In addition, astrogliosis also can provoke and further boost nerve cell damage, once it gets beyond control. Sex steroids have been demonstrated in different disease models to affect reactive gliosis and inhibit or dampen inflammatory processes perpetuated by astroglia [12,[30][31][32] . The main focus of attention in acute stroke research in recent years has been given to the function and regulation of local microglia and invaded blood-derived macrophages and T cells.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Induced Gene Expression of Aquaporin-4, Cyclooxygenase-2 and Hypoxia-Inducible Factor 1α in Rat Cortical Astroglia Is Inhibited by 17β-Estradiol and Progesterone

Habib¹,

Dang²,

Slowik³

et al. 2014

Neuroendocrinology

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17β-Estradiol (E₂) and progesterone (P) are neuroprotective in acute brain injury by attenuating neuropathophysiological processes and regulating local glial function. Besides controlling brain-intrinsic immune responses, astrocytes are cellular targets for sex steroids in health and disease and typically resist to hypoxic damage. In this in vitro study, we aimed at uncovering astroglia-specific reactions to sublethal hypoxic conditions and astroglia-specific effects of both sex steroid hormones on these parameters. Short-term hypoxia for 3 h increased reactive oxygen species production, but had no influence on cell viability of cerebral cortical rat astroglia. Astrocytes expressed classical estrogen receptors (ER), progesterone receptor (PR), and a set of nonclassical steroid hormone receptors. Hypoxia specifically induced ERα and PR isoform A gene expression. Oxygen deprivation increased gene expression of aquaporin-4 (AQP4), hypoxia-inducible factor 1α (Hif1α), and cyclooxygenase-2 (COX2). The application of E₂ and P selectively prevented this induction. Effects on protein levels of these genes appeared to be delayed. These data show that astrocytes change their receptivity for sex steroid hormones by switching steroid hormone receptor expression and that E₂ and P modify or antagonize proinflammatory COX2 synthesis, edema-promoting AQP4 expression, and the Hif1α increase. In vivo studies have to address whether these cell responses contribute to steroid-mediated neuroprotection in stroke.

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“…Thereby inhibits TLR4-mediated NF-κB signaling [49]. Microglia are the primary source of the pro-inflammatory cytokine and contributed to neuroinflammation [50,51]. Though we found expression of Sik1 in both microglia and neuron, we focused on microglia-mediated neuroinflammation in this study.…”

Section: Discussionmentioning

confidence: 89%

Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling

Zhang

Gao

Yang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Alcohol consumption has been shown to cause neuroinflammation and increase a variety of immune-related signaling processes. Microglia are a crucial part of alcohol-induced neuroinflammation and undergo apoptosis. Even though the importance of these inflammatory processes in the effects of alcohol-related neurodegeneration have been established, the mechanism of alcohol-induced microglia apoptosis is unknown. In prior research, we discovered that alcohol increases expression of salt-inducible kinase 1 (SIK1) in rodent brain tissue. In this study, we sought to determine what role SIK1 expression plays in alcohol-induced neuroinflammation as well as whether and by what mechanism it regulates microglia apoptosis. Methods: Adult C57BL/6 mice were divided into four groups and for 3 weeks treated with either 0%, 5%, 10%, or 15% alcohol during 3 hour periods. The mice were sacrificed and their brains excised for analysis. Additionally, primary microglia were isolated from neonatal mice. SIK1 expression in alcohol-treated brain tissue and microglia was analyzed via RT-PCR and western blotting. TUNEL staining, caspase-3, and caspase-9 activity assays were performed to evaluate microglial apoptosis. Cell fluorescence staining and NF-κB luciferase activity assays were used to evaluate the effects of SIK1 expression on the NF-κB signaling pathway. Results: SIK1 expression was increased in the brains of mice that consumed alcohol, and this effect was seen in mouse primary microglia. SIK1 knockdown in microglia increased alcohol-induced apoptosis in these cells. Furthermore, SIK1 reduced NF-κB signaling pathway factors, and SIK1 knockdown in microglia promoted alcohol-induced NF-κB activity. TUNEL staining, caspase-3, and caspase-9 activity assays consistently revealed that alcohol-induced microglial apoptosis was inhibited by depletion of p65. Finally, we determined that NF-κB signaling is required for alcohol-induced, SIK1-mediated apoptosis in microglia. Conclusion: This study establishes for the first time not only that SIK1 is crucial to regulating alcohol-induced microglial apoptosis, but also that the NF-κB signaling pathway is required for its activity. Overall, our results help elucidate mechanisms of alcohol-induced neuroinflammation.

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Neuroprotection by gonadal steroid hormones in acute brain damage requires cooperation with astroglia and microglia

Cited by 95 publications

References 159 publications

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

Poststroke Inflammasome Expression and Regulation in the Peri-Infarct Area by Gonadal Steroids after Transient Focal Ischemia in the Rat Brain

Hypoxia-Induced Gene Expression of Aquaporin-4, Cyclooxygenase-2 and Hypoxia-Inducible Factor 1α in Rat Cortical Astroglia Is Inhibited by 17β-Estradiol and Progesterone

Salt-Inducible Kinase 1 (SIK1) is Induced by Alcohol and Suppresses Microglia Inflammation via NF-κB Signaling

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