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HMGB1 is a Potential Mediator of Astrocytic TLR4 Signaling Activation following Acute and Chronic Focal Cerebral Ischemia.

ABSTRACT: Limited, and underutilized, therapeutic options for acute stroke require new approaches to treatment. One such potential approach involves better understanding of innate immune response to brain injury such as acute focal cerebral ischemia. This includes understanding the temporal profile, and specificity, of Toll-like receptor 4 (TLR4) signaling in brain cell types, such as astrocytes, following focal cerebral ischemia. This study evaluated TLR4 signaling, and downstream mediators, in astrocytes, during acute and chronic phases post transient middle cerebral artery occlusion (MCAO). We also determined whether high mobility group box 1 (HMGB1), an endogenous TLR4 ligand, was sufficient to induce TLR4 signaling activation in astrocytes in vivo and in vitro. We injected HMGB1 into normal cortex, in vivo, and stimulated cultured astrocytes with HMGB1, in vitro, and determined TLR4, and downstream mediator, expression by immunohistochemistry. We found that expression of TLR4, and downstream mediators, such as inducible nitric oxide synthase (iNOS), occurs in penumbral astrocytes in acute and chronic phases after focal cerebral ischemia, but was undetectable in cortical astrocytes in the contralateral hemisphere. In addition, cortical injection of recombinant HMGB1 led to a trend towards an almost 2-fold increase in TLR4 expression in astrocytes surrounding the injection site. Consistent with these results, in vitro stimulation of the DI TNC1 astrocyte cell line, with recombinant HMGB1, led to increased TLR4 and iNOS message levels. These findings suggest that HMGB1, an endogenous TLR4 ligand, is an important physiological ligand for TLR4 signaling activation, in penumbral astrocytes, following acute and chronic ischemia and HMGB1 amplifies TLR4 signaling in astrocytes.

SUBMITTER: Famakin BM

PROVIDER: S-EPMC7053497 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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HMGB1 is a Potential Mediator of Astrocytic TLR4 Signaling Activation following Acute and Chronic Focal Cerebral Ischemia.

Famakin Bolanle M BM Tsymbalyuk Orest O Tsymbalyuk Natalia N Ivanova Svetlana S Woo Seung Kyoon SK Kwon Min Seong MS Gerzanich Volodymyr V Simard J Marc JM

Neurology research international 20200220

Limited, and underutilized, therapeutic options for acute stroke require new approaches to treatment. One such potential approach involves better understanding of innate immune response to brain injury such as acute focal cerebral ischemia. This includes understanding the temporal profile, and specificity, of Toll-like receptor 4 (TLR4) signaling in brain cell types, such as astrocytes, following focal cerebral ischemia. This study evaluated TLR4 signaling, and downstream mediators, in astrocyte ...[more]

PMID: 32148958

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Project description:Background and purposeReperfusion after transient cerebral ischemia causes severe damage to mitochondria; however, little is known regarding the continuous change in mitochondrial biogenesis during reperfusion. Mitochondrial biogenesis causes an increase in the individual mitochondrial mass of neurons and maintains their aerobic set-point in the face of declining function. The aim of this study was to examine mitochondrial biogenesis in the cortex during reperfusion following focal cerebral ischemia.MethodsMale Wistar rats were subjected to transient focal cerebral ischemia. The relative amount of cortical mitochondrial DNA was analyzed using quantitative real-time PCR at 0 h, 24 h, 72 h, and 7 d after reperfusion. Three critical transcriptional regulators of mitochondrial biogenesis were measured by semi-quantitative reverse-transcription PCR. The protein expression of cytochrome C oxidase subunits I and IV was detected by Western blotting.ResultsEvidence of increased mitochondrial biogenesis was observed after reperfusion. The cortical mitochondrial DNA content increased after 24 h, peaked after 72 h, and maintained a high level for 7 d. The cortical expression of three critical genes for the transcriptional regulation of mitochondrial biogenesis, namely, peroxisome proliferator-activated receptor coactivator-1α, nuclear respiratory factor-1, and mitochondrial transcription factor A, also increased at 24 h and 72 h. The expression of peroxisome proliferator-activated receptor coactivator-1α returned to the baseline level at 7 d, but two other factors maintained higher levels compared with the controls. Moreover, the expression of cytochrome C oxidase subunits I and IV was increased in the cortex.ConclusionsThese results indicate that reperfusion increased mitochondrial biogenesis following focal cerebral ischemia, and this tendency was exacerbated as the reperfusion time was extended. Reperfusion-induced mitochondrial biogenesis was mediated through up-regulation of critical transcriptional regulators of mitochondrial biogenesis.

Project description:Stroke remains one of the leading causes of permanent disability and death worldwide. Apoptosis and autophagy are two key elements involved in ischemic brain damage. Ethanol is a commonly used and abused chemical substance that affects the prognosis of ischemic stroke. We determined the influence of chronic ethanol consumption on apoptosis and autophagy following transient focal cerebral ischemia. Male C57BL/6 J mice were randomly divided into three groups and gavage fed with 0.7 and 2.8 g/kg/day ethanol or volume-matched water daily for 8 weeks. DNA fragmentation, TUNEL-positive neurons, cleaved caspase-3-positive neurons, translocation of mitochondrial cytochrome C and apoptosis inducing factor (AIF), LC3B-positive neurons, and expression of LC3B, Beclin-1 and Bcl-2 in peri-infarct cortex were evaluated at 24 hours of reperfusion after a 90-minute unilateral middle cerebral artery occlusion (MCAO). Cerebral ischemia/reperfusion (I/R) injury was significantly improved in the 0.7 g/kg/d ethanol group but worsened in the 2.8 g/kg/d ethanol group. DNA fragmentation was significantly increased at 24 hours of reperfusion in all groups. However, the magnitude of the increase was significantly less in the 0.7 g/kg/d ethanol group. In addition, both cleaved caspase-3-positive neurons and TUNEL-positive neurons were significantly less in 0.7 g/kg/d ethanol group. Furthermore, translocation of mitochondrial cytochrome C and AIF was significantly alleviated in the 0.7 g/kg/d ethanol group. On the other hand, baseline expression of LC3B was significantly reduced in the 2.8 g/kg/d ethanol group. Post-ischemic expression of LC3B and LC3B-positive neurons were significantly attenuated in both 0.7 and 2.8 g/kg/d ethanol groups. Moreover, although post-ischemic expression of Beclin-1 was not altered in the ethanol groups, post-ischemic expression of Bcl-2 was significantly greater in both 0.7 and 2.8 g/kg/d ethanol groups. Our findings suggest that light ethanol consumption may protect against cerebral I/R injury by suppressing post-ischemic apoptosis, whereas heavy ethanol consumption may exacerbate cerebral I/R injury by suppressing autophagy.

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HMGB1 is a Potential Mediator of Astrocytic TLR4 Signaling Activation following Acute and Chronic Focal Cerebral Ischemia.

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HMGB1 is a Potential Mediator of Astrocytic TLR4 Signaling Activation following Acute and Chronic Focal Cerebral Ischemia.

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