Hypoxia-inducible factor-1α upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction

Huang, Tao; Huang, Weiyi; Zhang, Zhiqiang; Yu, Lei; Xie, Caijun; Zhu, Dongan; Peng, Zi-zhuang; Chen, Jiehan

doi:10.1097/wnr.0000000000000236

Cited by 38 publications

(26 citation statements)

References 23 publications

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“…Semi‐quantitative single‐cell PCR would be required to confirm this assumption. It is also conceivable that Kv channel activation is modulated by post‐transcriptional and post‐translational regulation (Huang et al, ) or by other mechanisms such as interaction with enzymes (Combs, Shin, Xu, Ramu, & Lu, ) or peptides (Feng et al, ; Xie et al, ). Based on our findings, Kv1.5 and in particular Kv3.1 are less likely to contribute to the observed upregulation of outward currents in plaque‐associated microglia.…”

Section: Discussionmentioning

confidence: 99%

Plaque‐dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model

Plescher

Seifert

Hansen

et al. 2018

Glia

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Microglia, the central nervous system resident innate immune cells, cluster around Aβ plaques in Alzheimer's disease (AD). The activation phenotype of these plaque-associated microglial cells, and their differences to microglia distant to Aβ plaques, are incompletely understood. We used novel three-dimensional cell analysis software to comprehensively analyze the morphological properties of microglia in the TgCRND8 mouse model of AD in spatial relation to Aβ plaques. We found strong morphological changes exclusively in plaque-associated microglia, whereas plaque-distant microglia showed only minor changes. In addition, patch-clamp recordings of microglia in acute cerebral slices of TgCRND8 mice revealed increased K currents in plaque-associated but not plaque-distant microglia. Within the subgroup of plaque-associated microglia, two different current profiles were detected. One subset of cells displayed only increased inward currents, while a second subset showed both increased inward and outward currents, implicating that the plaque microenvironment differentially impacts microglial ion channel expression. Using pharmacological channel blockers, multiplex single-cell PCR analysis and RNA fluorescence in situ hybridization, we identified Kir and Kv channel types contributing to the in- and outward K conductance in plaque-associated microglia. In summary, we have identified a previously unrecognized level of morphological and electrophysiological heterogeneity of microglia in relation to amyloid plaques, suggesting that microglia may display multiple activation states in AD.

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Section: Discussionmentioning

confidence: 99%

Plaque‐dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model

Plescher

Seifert

Hansen

et al. 2018

Glia

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“…The changes in vessel reactivity followed by reperfusion could induce hypoxic stress on the endothelium, resulting in BBBD (43). Molecular analysis following pFUS+MB-induced vasospasm (31) has not been investigated adequately, but the increases in protein expression or mRNA reported here in HSP70, TNFα, IL1α, IL1β, VEGF, and EPO would be consistent with decreased perfusion and reperfusion within the targeted parenchyma (9,12,19,(44)(45)(46)(47). The rapid increase in TNFα and other proinflammatory factors indicates an acute involvement of NVU elements in response to hypoxia or injury (14,48).…”

Section: Discussionmentioning

confidence: 99%

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Kovács

Kim

Jikaria

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

368

388

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MRI-guided pulsed focused ultrasound (pFUS) combined with systemic infusion of ultrasound contrast agent microbubbles (MB) causes localized blood-brain barrier (BBB) disruption that is currently being advocated for increasing drug or gene delivery in neurological diseases. The mechanical acoustic cavitation effects of opening the BBB by low-intensity pFUS+MB, as evidenced by contrast-enhanced MRI, resulted in an immediate damage-associated molecular pattern (DAMP) response including elevations in heat-shock protein 70, IL-1, IL-18, and TNFα indicative of a sterile inflammatory response (SIR) in the parenchyma. Concurrent with DAMP presentation, significant elevations in proinflammatory, antiinflammatory, and trophic factors along with neurotrophic and neurogenesis factors were detected; these elevations lasted 24 h. Transcriptomic analysis of sonicated brain supported the proteomic findings and indicated that the SIR was facilitated through the induction of the NFκB pathway. Histological evaluation demonstrated increased albumin in the parenchyma that cleared by 24 h along with TUNEL + neurons, activated astrocytes, microglia, and increased cell adhesion molecules in the vasculature. Infusion of fluorescent beads 3 d before pFUS+MB revealed the infiltration of CD68 + macrophages at 6 d postsonication, as is consistent with an innate immune response. pFUS+MB is being considered as part of a noninvasive adjuvant treatment for malignancy or neurodegenerative diseases. These results demonstrate that pFUS+MB induces an SIR compatible with ischemia or mild traumatic brain injury. Further investigation will be required before this approach can be widely implemented in clinical trials.pulsed focused ultrasound | microbubbles | blood-brain barrier | sterile inflammation | magnetic resonance imaging T he temporal proteomic profile in response to blood-brain barrier disruption (BBBD) consists of molecular features that are common across noninfectious insults such as ischemia, trauma, or autoimmune diseases (1-7). The main purpose of the bloodbrain barrier (BBB) is to maintain homeostasis, preventing the passive crossing of cells and molecules that could induce inflammation or damage to cells. The BBB consists of specialized endothelial cells connected through various tight junction proteins (TJP), astrocyte endplates, and a basement membrane. These components form part of the neurovascular unit (NVU) that is comprised of vessels, pericytes, microglia, astrocytes, and neurons along with the extracellular matrix (1,3,4,8). BBBD secondary to ischemia or trauma leads to increases in endothelial caveolae and down-regulation of TJP, transcytosis of plasma proteins (i.e., albumin), and vasogenic edema (1,6,(8)(9)(10)(11). The presence of albumin in the parenchyma following BBBD can activate astrocytes and microglia and induce the production of cytokines, chemokines, and trophic factors (CCTFs) and cell adhesion molecules (CAMs) as observed with a sterile inflammatory response (SIR) to injury (12-15). The release of CCTFs and inte...

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“…The neuroprotective effects of HP are mediated via the transcription factor hypoxia-inducible factor-1 (HIF-1) (Bergeron et al, 2000;Sharp et al, 2001) and various target genes, which initiate angiogenesis, erythropoiesis, glucose store mobilization and therefore, cell survival. Recent studies have shown the protective effects of hypoxia to be mediated by HIF-1␣, where knockout mice were not protected by HP (Sheldon et al, 2014), and pharmacological blockade of HIF-1 was able to prevent hypoxia-induced microglial activation (Huang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Hypoxic preconditioning can reduce injury‐induced inflammatory processes in the neonatal rat brain

Parmar

Jones

2015

Intl J of Devlp Neuroscience

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Inflammation plays an important role in the pathophysiology of neonatal hypoxic-ischemic (HI) brain injury. Studies have shown that hypoxic preconditioning (HP) can ameliorate brain damage, but its effects on inflammation remain unknown. Postnatal day 6 (P6), Sprague-Dawley rats were divided into normoxia and hypoxia (8% oxygen, 3h) groups. On P7, some pups underwent a right carotid artery occlusion followed by hypoxia (8% oxygen, 3h) while under 1.5% isofluorane anesthesia and the remaining pups underwent sham surgery without occlusion. Animals were sacrificed 5 days later and fixed tissue was used to examine changes in neurons, astrocytes, and microglia in the cortex. Fresh tissue was collected to determine cortical levels of proinflammatory cytokines using ELISA. There was a significant loss in the number of NeuN positive cells in the cortex following HI injury, which was improved when HP was given prior to HI. There was an increase in cortical area of astrocyte staining after HI injury compared to control. HP before HI was able to reduce area of GFAP staining back to control levels. HI caused a large increase in the number of activated microglia compared to control and HP was able to significantly reduce this, although not back to control levels. HP alone increased microglial activation. Interleukin-1β levels were increased in the cortex 5 days after HI, but HP was not able to significantly reduce this change. The neuroprotective effects of HP appear to be mediated by affecting cellular inflammatory processes in the brain following HI injury.

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Hypoxia-inducible factor-1α upregulation in microglia following hypoxia protects against ischemia-induced cerebral infarction

Cited by 38 publications

References 23 publications

Plaque‐dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model

Plaque‐dependent morphological and electrophysiological heterogeneity of microglia in an Alzheimer's disease mouse model

Disrupting the blood–brain barrier by focused ultrasound induces sterile inflammation

Hypoxic preconditioning can reduce injury‐induced inflammatory processes in the neonatal rat brain

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