Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia

Lian, Lu; Yun-sha, Zhang; Liu, Lu; Yang, Liji; Cai, Yichen; Zhang, Junping; Xu, Shixin

doi:10.3389/fnmol.2020.612439

Cited by 42 publications

(40 citation statements)

References 136 publications

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“…Currently, numerous studies have suggested that activated microglia with distinct phenotypes are double-edged swords in ischemic stroke (Liu ZJ. et al, 2019;Zhang et al, 2019;Lian et al, 2020). Differential polarization of microglia could likely explain the biphasic role of microglia in brain ischemia.…”

Section: Introductionmentioning

confidence: 99%

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

et al. 2021

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Monocyte locomotion inhibitory factor (MLIF) is a heat-stable pentapeptide from Entamoeba histolytica. Our previous study found that MLIF protects against ischemic stroke in rats and mice and exerts a neuroprotection effect in human neuroblastoma SH-SY5Y cells. Microglia/macrophage polarization has been proven to be vital in the pathology of ischemic stroke. Nevertheless, whether MLIF is able to modulate microglia/macrophage polarization remains unclear. We performed middle cerebral artery occlusion (MCAO) on C57BL/6J male mice and induced cultured BV2 microglia by oxygen-glucose deprivation (OGD), respectively. Immunfluorescence was utilized to detect the M1/2 markers, such as CD206 and CD16/32. qPCR and ELISA were used to detect the signature gene change of M1/2. The MAPK and NF-κB pathway associated proteins were measured by Western blot. To identify the protein target of MLIF, a pull-down assay was performed. We found that MLIF promoted microglia transferring from a “sick” M1 phenotype to a “healthy” M2 phenotype in vivo or in vitro. Furthermore, we proved that eukaryotic elongation factor 1A1 (eEF1A1) was involved in the modulation of microglia/macrophage polarization. Knocking down eEF1A1 by siRNA exhibited the M1 promotion effect and M2 inhibition effect. Taken together, our results demonstrated MLIF modulated microglia/macrophage polarization by targeting eEF1A1 in ischemic stroke.

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Section: Introductionmentioning

confidence: 99%

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

et al. 2021

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“…Additionally, microglia are known to respond to excitotoxic insult, ischemia, and reperfusion. In fact, microglia have been implicated in the exacerbation of damage following glutamate excitotoxicity and ischemic stroke, due to increased production of ROS and pro-inflammatory mediators ( Ma et al, 2017 ; Qin et al, 2019 ; Lian et al, 2020 ). At the same time, microglia also play an important protective role following tissue stroke damage, so the duality of their contribution to physiology/pathophysiology cannot be over-simplified to just a negative contribution to damage ( Ma et al, 2017 ; Qin et al, 2019 ; Marino Lee et al, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

Hayes

Ashmore

Vijayasankar

et al. 2021

Front. Aging Neurosci.

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The age-related reduction in circulating levels of insulin-like growth factor-1 (IGF-1) is associated with increased risk of stroke and neurodegenerative diseases in advanced age. Numerous reports highlight behavioral and physiological deficits in blood-brain barrier function and neurovascular communication when IGF-1 levels are low. Administration of exogenous IGF-1 reduces the extent of tissue damage and sensorimotor deficits in animal models of ischemic stroke, highlighting the critical role of IGF-1 as a regulator of neurovascular health. The beneficial effects of IGF-1 in the nervous system are often attributed to direct actions on neurons; however, glial cells and the cerebrovasculature are also modulated by IGF-1, and systemic reductions in circulating IGF-1 likely influence the viability and function of the entire neuro-glio-vascular unit. We recently observed that reduced IGF-1 led to impaired glutamate handling in astrocytes. Considering glutamate excitotoxicity is one of the main drivers of neurodegeneration following ischemic stroke, the age-related loss of IGF-1 may also compromise neural function indirectly by altering the function of supporting glia and vasculature. In this study, we assess and compare the effects of IGF-1 signaling on glutamate-induced toxicity and reactive oxygen species (ROS)-produced oxidative stress in primary neuron, astrocyte, and brain microvascular endothelial cell cultures. Our findings verify that neurons are highly susceptible to excitotoxicity, in comparison to astrocytes or endothelial cells, and that a prolonged reduction in IGFR activation increases the extent of toxicity. Moreover, prolonged IGFR inhibition increased the susceptibility of astrocytes to glutamate-induced toxicity and lessened their ability to protect neurons from excitotoxicity. Thus, IGF-1 promotes neuronal survival by acting directly on neurons and indirectly on astrocytes. Despite increased resistance to excitotoxic death, both astrocytes and cerebrovascular endothelial cells exhibit acute increases in glutamate-induced ROS production and mitochondrial dysfunction when IGFR is inhibited at the time of glutamate stimulation. Together these data highlight that each cell type within the neuro-glio-vascular unit differentially responds to stress when IGF-1 signaling was impaired. Therefore, the reductions in circulating IGF-1 observed in advanced age are likely detrimental to the health and function of the entire neuro-glio-vascular unit.

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“…Neuroinflammation, an inflammatory reaction occurring within the central nervous system (CNS), extensively participates in pathological processes in the CNS [1][2][3]. Microglia, the principal resident immune cells in CNS that account for approximately 10% of brain parenchymal cells, act as the main executor of neuroinflammation [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

PDCD4 Simultaneously Promotes Microglia Activation via PDCD4–MAPK–NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation

et al. 2021

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Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared key regulatory molecules and thus explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H 2 O 2 -induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic proteins BAX and Cleaved-PARP, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4-MAPK-NF-κB positive feedback loop may act as pivotal signaling for neuroinflammation which subsequently exaggerates neuronal injury, and thus may become a potential therapeutic target for neuroinflammatory diseases.

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Neuroinflammation in Ischemic Stroke: Focus on MicroRNA-mediated Polarization of Microglia

Cited by 42 publications

References 136 publications

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

MLIF Modulates Microglia Polarization in Ischemic Stroke by Targeting eEF1A1

Insulin-Like Growth Factor-1 Differentially Modulates Glutamate-Induced Toxicity and Stress in Cells of the Neurogliovascular Unit

PDCD4 Simultaneously Promotes Microglia Activation via PDCD4–MAPK–NF-κB Positive Loop and Facilitates Neuron Apoptosis During Neuroinflammation

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