A1 astrocytes activated by 2-Chloroethanol via the ROS-induced p38 MAPK/NF-κB and AP-1 pathways modulate microglia polarization

2021 ◽  
Author(s):  
Tong Wang ◽  
Qi Sun ◽  
Hongge Tang ◽  
Gaoyang Wang ◽  
Fenghong Zhao ◽  
...  
Keyword(s):  
Brain Edema ◽  
P38 Mapk ◽  
Reactive Astrocytes ◽  
Toxic Encephalopathy ◽  
Organic Chemical ◽  
M1 Polarization ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Rat Astrocytes ◽  
The Brain

Abstract Background1,2-Dichloroethane (1,2-DCE) is a synthetic organic chemical that causes brain edema under subacute poisoning. Our previous studies indicated that the neuroinflammation could be induced due to activation of both astrocytes and microglia during the course of brain edema in 1,2-DCE intoxicated mice. However, the crosstalk between the two glial cells in 1,2-DCE-induced neuroinflammation is unclear. In the current studies, we hypothesized that astrocytes are the first responder to the effects of 1,2-DCE in the brain, as they adhere to the cerebral capillaries, and they are an essential component of the blood-brain barrier (BBB).MethodsWe used primary cultured rat astrocytes and microglia, as well as a highly aggressively proliferating immortalized (HAPI) microglia cell line to study the effects of astrocytes on microglia polarization following exposure to 2-CE.ResultsFindings from the present studies demonstrated that treatment of primary rat astrocytes with 2-chloroethanol (2-CE), the intermediate metabolite of 1,2-DCE in vivo, can stimulate the activation of A1 reactive astrocytes (A1s) through p38 mitogen-activated protein kinase (p38 MAPK)/ nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways by the reactive oxygen species (ROS) produced during 2-CE metabolism. A1s activated by 2-CE can upregulate the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), and stimulate the M1 polarization of microglia through IL-1β and TNF-α released by 2-CE activated A1s. Microglia are less sensitive to 2-CE than astrocytes, since treatment of primary rat microglia with 30 mM 2-CE alone failed to activate them, though this dose of 2-CE can activate A1s and in turn stimulate M1 polarization of microglia through the factors released by A1s.ConclusionThe neuroinflammation induced by 1,2-DCE in the brain of mice is most probably triggered by the activation of astrocytes. The understanding of the multidimensional roles of reactive astrocytes may further the development of new treatment strategies in reducing neuroinflammation and brain edema following 1,2-DCE-induced toxic encephalopathy.

scholarly journals A1 Reactive Astrocytes Activated by 2-chloroethanol Modulate M1 Microglia Polarization through Upregulating IL-1β and TNF-α

2021 ◽  
Author(s):  
Tong Wang ◽  
Qi Sun ◽  
Hongge Tang ◽  
Gaoyang Wang ◽  
Fenghong Zhao ◽  
...  
Keyword(s):  
Brain Edema ◽  
Reactive Astrocytes ◽  
Mitogen Activated Protein Kinase ◽  
Toxic Encephalopathy ◽  
Organic Chemical ◽  
M1 Polarization ◽  
Tnf Α ◽  
Microglia Polarization ◽  
Rat Astrocytes ◽  
The Brain

Abstract Background1,2-Dichloroethane (1,2-DCE) is a synthetic organic chemical that causes brain edema under subacute poisoning. Our previous studies indicated that the neuroinflammation could be induced due to activation of both astrocytes and microglia during the course of brain edema in 1,2-DCE intoxicated mice. However, the crosstalk between the two glial cells in 1,2-DCE-induced neuroinflammation is unclear. In the current studies, we hypothesized that astrocytes are the first responder to the effects of 1,2-DCE in the brain, as they adhere to the cerebral capillaries, and they are an essential component of the blood-brain barrier (BBB).MethodsWe used primary cultured rat astrocytes and microglia, as well as a highly aggressively proliferating immortalized (HAPI) microglia cell line to study the effects of astrocytes on microglia polarization following exposure to 2-CE. ResultsFindings from the present studies demonstrated that treatment of primary rat astrocytes with 2-chloroethanol (2-CE), the intermediate metabolite of 1,2-DCE in vivo, can stimulate the activation of A1 reactive astrocytes (A1s) through p38 mitogen-activated protein kinase (p38 MAPK)/ nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways by the reactive oxygen species (ROS) produced during 2-CE metabolism. A1s activated by 2-CE can upregulate the expression of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS), and stimulate the M1 polarization of microglia through IL-1β and TNF-α released by 2-CE activated A1s. Microglia are less sensitive to 2-CE than astrocytes, since treatment of primary rat microglia with 30 mM 2-CE alone failed to activate them, though this dose of 2-CE can activate A1s and in turn stimulate M1 polarization of microglia through the factors released by A1s. ConclusionThe neuroinflammation induced by 1,2-DCE in the brain of mice is most probably triggered by the activation of astrocytes. The understanding of the multidimensional roles of reactive astrocytes may further the development of new treatment strategies in reducing neuroinflammation and brain edema following 1,2-DCE-induced toxic encephalopathy.

scholarly journals Roles of Crosstalk between Astrocytes and Microglia in Triggering Neuroinflammation and Brain Edema Formation in 1,2-Dichloroethane-Intoxicated Mice

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2647
Author(s):  
Jinhan Yang ◽  
Tong Wang ◽  
Xiaoxia Jin ◽  
Gaoyang Wang ◽  
Fenghong Zhao ◽  
...  
Keyword(s):  
Protein Expression ◽  
Brain Edema ◽  
Adhesion Molecule ◽  
Calcium Binding ◽  
Microglial Activation ◽  
Reactive Astrocytes ◽  
Edema Formation ◽  
Expression Levels ◽  
Tnf Α ◽  
Brain Edema Formation

We have previously reported that the activation of astrocytes and microglia may lead to the overproduction of proinflammatory mediators, which could induce neuroinflammation and cause brain edema in 1,2-dichloroethane (1,2-DCE)-intoxicated mice. In this research, we further hypothesized that astrocyte–microglia crosstalk might trigger neuroinflammation and contribute to brain edema in 1,2-DCE-intoxicated mice. The present research revealed, for the first time, that subacute intoxication with 1,2-DCE might provoke the proinflammatory polarization of microglia, and pretreatment with minocycline, a specific inhibitor of microglial activation, may attenuate the enhanced protein levels of ionized calcium-binding adapter molecule1 (Iba-1), cluster of differentiation 11b (CD11b), glial fibrillary acidic protein (GFAP), soluble calcium-binding protein 100B (S100B), tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), inducible nitric oxide synthase (iNOS), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), matrix metalloproteinase-9 (MMP-9), Toll-like receptor 4 (TLR4), MyD88, and p-p65, and ameliorate the suppressed protein expression levels of occludin and claudin 5; we also observed changes in water content and made pathological observations on edema in the brains of 1,2-DCE-intoxicated mice. Moreover, pretreatment with fluorocitrate, an inhibitor of reactive astrocytes, could also reverse the alteration in protein expression levels of GFAP, S100B, Iba-1, CD11b, TNF-α, IL-6, iNOS, VCAM-1, ICAM-1, MMP-9, occludin, and claudin 5 in the brain of 1,2-DCE intoxicated mice. Furthermore, pretreatment with melatonin, a well-known anti-inflammatory drug, could also attenuate the above-mentioned changes in the brains of 1,2-DCE-intoxicated mice. Altogether, the findings from this research indicated that microglial activation might play an important role in triggering neuroinflammation, and hence may contribute to brain edema formation; additionally, the findings suggested that molecular crosstalk between reactive astrocytes and activated microglia may amplify the neuroinflammatory reaction, which could induce secondary brain injury in 1,2-DCE-intoxicated mice.

Reactive astrocytes induced by 2-chloroethanol modulate microglia polarization through IL-1β, TNF-α, and iNOS upregulation

2021 ◽  
pp. 112550
Author(s):  
Tong Wang ◽  
Qi Sun ◽  
Jinhan Yang ◽  
Gaoyang Wang ◽  
Fenghong Zhao ◽  
...  
Keyword(s):  
Reactive Astrocytes ◽  
Tnf Α ◽  
Microglia Polarization

scholarly journals Neuroinflammatory Reactions in the Brain of 1,2-DCE-Intoxicated Mice during Brain Edema

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 987 ◽  
Author(s):  
Xiaoxia Jin ◽  
Tong Wang ◽  
Yingjun Liao ◽  
Jingjing Guo ◽  
Gaoyang Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Brain Edema ◽  
P38 Mapk ◽  
Adhesion Molecule ◽  
Calcium Binding ◽  
Mapk Signaling ◽  
Intercellular Adhesion Molecule ◽  
Inflammatory Reactions ◽  
Protein Levels ◽  
The Brain

We previously reported that expression of matrix metalloproteinase-9 (MMP-9) mRNA and protein was upregulated during 1,2-dichloroethane (1,2-DCE) induced brain edema in mice. We also found that the p38 mitogen-activated protein kinase (p38 MAPK) signaling pathway resulted in MMP-9 overexpression and nuclear factor-κB (NF-κB) activation in mice treated with 1,2-DCE. In this study, we further hypothesized that inflammatory reactions mediated by the p38 MAPK/ NF-κB signaling pathway might be involved in MMP-9 overexpression, blood–brain barrier (BBB) disruption and edema formation in the brain of 1,2-DCE-intoxicated mice. Our results revealed that subacute poisoning by 1,2-DCE upregulates protein levels of glial fibrillary acidic protein (GFAP), ionized calcium-binding adapter molecule 1 (Iba-1), interleukin-1β (IL-1β), vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), inducible nitric oxide synthase (iNOS) and p-p65 in mouse brains. Pretreatment with an inhibitor against p38 MAPK attenuates these changes. Moreover, pretreatment with an inhibitor against NF-κB attenuates alterations in brain water content, pathological indications notable in brain edema, as well as mRNA and protein expression on levels of MMP-9, VCAM-1, ICAM-1, iNOS, and IL-1β, tight junction proteins (TJs), GFAP and Iba-1 in the brain of 1,2-DCE-intoxicated mice. Furthermore, pretreatment with an inhibitor against MMP-9 obstructs the decrease of TJs in the brain of 1,2-DCE-intoxicated mice. Lastly, pretreatment with an antagonist against the IL-1β receptor also attenuates changes in protein levels of p-p38 MAPK, p-p65, p-IκB, VCAM -1, ICAM-1, IL-1β, and Iba-1 in the brain of 1,2-DCE-intoxicated-mice. Taken together, findings from the current study indicate that the p38 MAPK/ NF-κB signaling pathway might be involved in the activation of glial cells, and the overproduction of proinflammatory factors, which might induce inflammatory reactions in the brain of 1,2-DCE-intoxicated mice that leads to brain edema.

scholarly journals Direct Evidence for Central Proinflammatory Mechanisms in Rats with Experimental Acute Liver Failure: Protective Effect of Hypothermia

2009 ◽  
Vol 29 (5) ◽  
pp. 944-952 ◽  
Author(s):  
Wenlei Jiang ◽  
Paul Desjardins ◽  
Roger F Butterworth
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Brain Edema ◽  
Proinflammatory Cytokines ◽  
Direct Evidence ◽  
Mild Hypothermia ◽  
Tnf Α ◽  
Factor Α ◽  
The Brain ◽  
Necrosis Factor

It has been proposed that proinflammatory mechanisms are involved in the pathogenesis of brain edema in acute liver failure (ALF). The aim of this study was to assess the contribution of cerebral inflammation to the neurologic complications of ALF and to assess the antiinflammatory effect of mild hypothermia. Upregulation of CD11b/c immunoreactivity, consistent with microglial activation, was observed in the brains of ALF rats at coma stages of encephalopathy. Interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) mRNAs were increased two to threefold in the brains of ALF rats compared with that in sham-operated controls. The magnitude of increased expression of proinflammatory cytokines in the brain was correlated with the progression of encephalopathy and the onset of brain edema. Significant increases in IL-1β, IL-6, and TNF-α levels were also found in the sera and cerebrospinal fluid (CSF) of these animals. Mild hypothermia delayed the onset of encephalopathy, prevented brain edema, and concomitantly attenuated plasma, brain, and CSF proinflammatory cytokines. These results show that experimental ALF leads to increases in brain production of proinflammatory cytokines, and afford the first direct evidence that central inflammatory mechanisms play a role in the pathogenesis of the cerebral complications of ALF. Antiinflammatory agents could be beneficial in the management of these complications.

Endothelin systems in the brain: involvement in pathophysiological responses of damaged nerve tissues

2013 ◽  
Vol 4 (4) ◽  
pp. 335-347 ◽  
Author(s):  
Yutaka Koyama
Keyword(s):  
Brain Edema ◽  
Neurotrophic Factors ◽  
Cerebral Arteries ◽  
Chronic Phase ◽  
Neural Progenitors ◽  
Reactive Astrocytes ◽  
Brain Disorders ◽  
Pharmacological Significance ◽  
And Migration ◽  
The Brain

AbstractIn addition to their potent vasoconstriction effects, endothelins (ETs) show multiple actions in various tissues including the brain. The brain contains high levels of ETs, and their production is stimulated in many brain disorders. Accumulating evidence indicates that activation of brain ET receptors is involved in several pathophysiological responses in damaged brains. In this article, the roles of brain ET systems in relation to brain disorders are reviewed. In the acute phase of stroke, prolonged vasospasm of cerebral arteries and brain edema occur, both of which aggravate brain damage. Studies using ET antagonists show that activation of ETA receptors in the brain vascular smooth muscle induces vasospasm after stroke. Brain edema is induced by increased activity of vascular permeability factors, such as vascular endothelial growth factor and matrix metalloproteinases. Activation of ETB receptors stimulates astrocytic production of these permeability factors. Increases in reactive astrocytes are observed in neurodegenerative diseases and in the chronic phase of stroke, where they facilitate the repair of damaged nerve tissues by releasing neurotrophic factors. ETs promote the induction of reactive astrocytes through ETB receptors. ETs also stimulate the production of astrocytic neurotrophic factors. Recent studies have shown high expression of ETB receptors in neural progenitors. Activation of ETB receptors in neural progenitors promotes their proliferation and migration, suggesting roles for ETB receptors in neurogenesis. Much effort has been invested in the pursuit of novel drugs to induce protection or repair of damaged nerve tissues. From these studies, the pharmacological significance of brain ET systems as a possible target of neuroprotective drugs is anticipated.

Activation of Melanocortin-4 Receptor by a Synthetic Agonist Inhibits Ethanolinduced Neuroinflammation in Rats

2020 ◽  
Vol 25 (45) ◽  
pp. 4799-4805 ◽  
Author(s):  
Osvaldo Flores-Bastías ◽  
Gonzalo I. Gómez ◽  
Juan A. Orellana ◽  
Eduardo Karahanian
Keyword(s):  
Prefrontal Cortex ◽  
Alcohol Consumption ◽  
Ethanol Intake ◽  
Neuroinflammatory Response ◽  
Agonist Peptide ◽  
Melanocortin 4 Receptor ◽  
Tnf Α ◽  
Cord Injury ◽  
High Ethanol ◽  
The Brain

Background: High ethanol intake induces a neuroinflammatory response resulting in the subsequent maintenance of chronic alcohol consumption. The melanocortin system plays a pivotal role in the modulation of alcohol consumption. Interestingly, it has been shown that the activation of melanocortin-4 receptor (MC4R) in the brain decreases the neuroinflammatory response in models of brain damage other than alcohol consumption, such as LPS-induced neuroinflammation, cerebral ischemia, glutamate excitotoxicity, and spinal cord injury. Objectives: In this work, we aimed to study whether MC4R activation by a synthetic MC4R-agonist peptide prevents ethanol-induced neuroinflammation, and if alcohol consumption produces changes in MC4R expression in the hippocampus and hypothalamus. Methods: Ethanol-preferring Sprague Dawley rats were selected offering access to 20% ethanol on alternate days for 4 weeks (intermittent access protocol). After this time, animals were i.p. administered an MC4R agonist peptide in the last 2 days of the protocol. Then, the expression of the proinflammatory cytokines interleukin 6 (IL-6), interleukin 1-beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) were measured in the hippocampus, hypothalamus and prefrontal cortex. It was also evaluated if ethanol intake produces alterations in the expression of MC4R in the hippocampus and the hypothalamus. Results: Alcohol consumption increased the expression of MC4R in the hippocampus and the hypothalamus. The administration of the MC4R agonist reduced IL-6, IL-1β and TNF-α levels in hippocampus, hypothalamus and prefrontal cortex, to those observed in control rats that did not drink alcohol. Conclusion: High ethanol consumption produces an increase in the expression of MC4R in the hippocampus and hypothalamus. The administration of a synthetic MC4R-agonist peptide prevents neuroinflammation induced by alcohol consumption in the hippocampus, hypothalamus, and prefrontal cortex. These results could explain the effect of α-MSH and other synthetic MC4R agonists in decreasing alcohol intake through the reduction of the ethanol-induced inflammatory response in the brain.

Inhibition of microRNA-155 Alleviates Neurological Dysfunction Following Transient Global Ischemia and Contribution of Neuroinflammation and Oxidative Stress in the Hippocampus

2020 ◽  
Vol 25 (40) ◽  
pp. 4310-4317 ◽  
Author(s):  
Lichao Sun ◽  
Shouqin Ji ◽  
Jihong Xing
Keyword(s):  
Oxidative Stress ◽  
Brain Edema ◽  
Severity Score ◽  
Global Ischemia ◽  
Signal Pathways ◽  
Neurological Severity Score ◽  
Tnf Α ◽  
Transient Global Ischemia ◽  
And Oxidative Stress

Background/Aims: Central pro-inflammatory cytokine (PIC) signal is involved in neurological deficits after transient global ischemia induced by cardiac arrest (CA). The present study was to examine the role of microRNA- 155 (miR-155) in regulating IL-1β, IL-6 and TNF-α in the hippocampus of rats with induction of CA. We further examined the levels of products of oxidative stress 8-isoprostaglandin F2α (8-iso PGF2α, indication of oxidative stress); and 8-hydroxy-2’-deoxyguanosine (8-OHdG, indication of protein oxidation) after cerebral inhibition of miR-155. Methods: CA was induced by asphyxia and followed by cardiopulmonary resuscitation in rats. ELISA and western blot analysis were used to determine the levels of PICs and products of oxidative stress; and the protein expression of NADPH oxidase (NOXs) in the hippocampus. In addition, neurological severity score and brain edema were examined to assess neurological functions. Results: We observed amplification of IL-1β, IL-6 and TNF-α along with 8-iso PGF2α and 8-OHdG in the hippocampus of CA rats. Cerebral administration of miR-155 inhibitor diminished upregulation of PICs in the hippocampus. This also attenuated products of oxidative stress and upregulation of NOX4. Notably, inhibition of miR-155 improved neurological severity score and brain edema and this was linked to signal pathways of PIC and oxidative stress. Conclusion: We showed the significant role of blocking miR-155 signal in improving the neurological function in CA rats likely via inhibition of signal pathways of neuroinflammation and oxidative stress, suggesting that miR-155 may be a target in preventing and/or alleviating development of the impaired neurological functions during CA-evoked global cerebral ischemia.

The Impact of Royal Jelly against Hepatic Ischemia/Reperfusion-Induced Hepatocyte Damage in Rats: The Role of Cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α Signaling Pathways

2020 ◽  
Vol 14 (1) ◽  
pp. 88-100
Author(s):  
Fares E.M. Ali ◽  
Heba M. Saad Eldien ◽  
Nashwa A.M. Mostafa ◽  
Abdulrahman H. Almaeen ◽  
Mohamed R.A. Marzouk ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
P38 Mapk ◽  
Royal Jelly ◽  
Ischemia Reperfusion ◽  
Histopathological Changes ◽  
Down Regulation ◽  
Hepatic Ischemia ◽  
Tnf Α ◽  
Hepatic Ischemia Reperfusion ◽  
The Impact

Objective: The present study was conducted to elucidate the underlying molecular mechanism as well as the potential hepatoprotective effects of royal jelly (RJ) against hepatic ischemia/reperfusion (IR) injury. Methods: Rats were assigned into four groups; sham (received vehicle), IR (30 minutes ischemia and 45 minutes reperfusion), sham pretreated with RJ (200 mg/kg P.O.), and IR pretreated with RJ (200 mg/kg P.O.). The experiment has lasted for 28 days. Results: Hepatic IR significantly induced hepatic dysfunctions, as manifested by elevation of serum transaminases, ALP and LDH levels. Moreover, hepatic IR caused a significant up-regulation of P38-MAPK, NF-κB-p65, TNF-α and MDA levels along with marked down-regulation of Nrf-2, HO-1, COX-4, cytoglobin, IκBa, IL-10, GSH, GST and SOD levels. Additionally, marked histopathological changes were observed after hepatic IR injury. On the contrary, pretreatment with RJ significantly improved hepatic functions along with the alleviation of histopathological changes. Moreover, RJ restored oxidant/antioxidant balance as well as hepatic expressions of Nrf-2, HO-1, COX-4, and cytoglobin. Simultaneously, RJ significantly mitigated the inflammatory response by down-regulation of P38-MAPK, NF-κB-p65, TNF-α expression. Conclusion: The present results revealed that RJ has successfully protected the liver against hepatic IR injury through modulation of cytoglobin, Nrf-2/HO-1/COX-4, and P38-MAPK/NF-κB-p65/TNF-α signaling pathways.

scholarly journals Ulinastatin alleviates traumatic brain injury by reducing endothelin-1

2020 ◽  
Vol 12 (1) ◽  
pp. 001-008
Author(s):  
Ting Liu ◽  
Xing-Zhi Liao ◽  
Mai-Tao Zhou
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Western Blot ◽  
Water Content ◽  
Brain Edema ◽  
Rat Model ◽  
Neurosurgical Procedures ◽  
Brain Water Content ◽  
The Brain ◽  
Brain Water

Abstract Background Brain edema is one of the major causes of fatality and disability associated with injury and neurosurgical procedures. The goal of this study was to evaluate the effect of ulinastatin (UTI), a protease inhibitor, on astrocytes in a rat model of traumatic brain injury (TBI). Methodology A rat model of TBI was established. Animals were randomly divided into 2 groups – one group was treated with normal saline and the second group was treated with UTI (50,000 U/kg). The brain water content and permeability of the blood–brain barrier were assessed in the two groups along with a sham group (no TBI). Expression of the glial fibrillary acidic protein, endthelin-1 (ET-1), vascular endothelial growth factor (VEGF), and matrix metalloproteinase 9 (MMP-9) were measured by immunohistochemistry and western blot. Effect of UTI on ERK and PI3K/AKT signaling pathways was measured by western blot. Results UTI significantly decreased the brain water content and extravasation of the Evans blue dye. This attenuation was associated with decreased activation of the astrocytes and ET-1. UTI treatment decreased ERK and Akt activation and inhibited the expression of pro-inflammatory VEGF and MMP-9. Conclusion UTI can alleviate brain edema resulting from TBI by inhibiting astrocyte activation and ET-1 production.

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