Microglia‐Derived Macrophage Colony Stimulating Factor Promotes Generation of Proinflammatory Cytokines by Astrocytes in the Periventricular White Matter in the Hypoxic Neonatal Brain

Deng, Yi; Lu, Jia; Ling, Eng‐Ang; Kaur, Charanjit

doi:10.1111/j.1750-3639.2010.00387.x

Cited by 34 publications

(34 citation statements)

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“…Interestingly, microglial activation was sustained up to nearly a week, suggesting that it is a persistent and intense inflammatory response in the CC in septic rats. Furthermore, at a late stage of the inflammatory response, the reactive astrocytes would be an additional cellular source for IL-1β [54]. Besides IL-1β, activated microglia release other proinflammatory mediators in adverse conditions including TNF-α, inducible nitric oxide synthase (iNOS), and NO; all these have been reported to cause the loss of oligodendrocyte and myelination deficit through the corresponding signaling pathways [19, 28, 55].…”

Section: Discussionmentioning

confidence: 99%

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

Han

Lin

Huang

et al. 2017

J Neuroinflammation

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BackgroundAxon development plays a pivotal role in the formation of synapse, nodes of Ranvier, and myelin sheath. Interleukin-1β (IL-1β) produced by microglia may cause myelination disturbances through suppression of oligodendrocyte progenitor cell maturation in the septic neonatal rats. Here, we explored if a microglia-derived IL-1β would disturb axon development in the corpus callosum (CC) following lipopolysaccharide (LPS) administration, and if so, whether it is associated with disorder of synapse formation in the cerebral cortex and node of Ranvier.MethodsSprague-Dawley rats (1-day old) in the septic model group were intraperitoneally administrated with lipopolysaccharide (1 mg/kg) and then sacrificed for detection of IL-1β, interleukin-1 receptor (IL-1R1), neurofilament-68, neurofilament-160, and neurofilament-200, proteolipid, synaptophysin, and postsynaptic density 95 (PSD95) expression by western blotting and immunofluorescence. Electron microscopy was conducted to observe alterations of axonal myelin sheath and synapses in the cortex, and proteolipid expression was assessed using in situ hybridization. The effect of IL-1β on neurofilament and synaptophysin expression in primary neuron cultures was determined by western blotting and immunofluorescence. P38-MAPK signaling pathway was investigated to determine whether it was involved in the inhibition of IL-1β on neurofilament and synaptophysin expression.ResultsIn 1-day old septic rats, IL-1β expression was increased in microglia coupled with upregulated expression of IL-1R1 on the axons. The expression of neurofilament-68, neurofilament-160, and neurofilament-200 (NFL, NFM, NFH) and proteolipid (PLP) was markedly reduced in the CC at 7, 14, and 28 days after LPS administration. Simultaneously, cortical synapses and mature oligodendrocytes were significantly reduced. By electron microscopy, some axons showed smaller diameter and thinner myelin sheath with damaged ultrastructure of node of Ranvier compared with the control rats. In the cerebral cortex of LPS-injected rats, some axo-dendritic synapses appeared abnormal looking as manifested by the presence of swollen and clumping of synaptic vesicles near the presynaptic membrane. In primary cultured neurons incubated with IL-1β, expression of NFL, NFM, and synaptophysin was significantly downregulated. Furthermore, p38-MAPK signaling pathway was implicated in disorder of axon development and synaptic deficit caused by IL-1β treatment.ConclusionsThe present results suggest that microglia-derived IL-1β might suppress axon development through activation of p38-MAPK signaling pathway that would contribute to formation disorder of cortical synapses and node of Ranvier following LPS exposure.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-017-0805-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

Han

Lin

Huang

et al. 2017

J Neuroinflammation

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“…Inflammation triggered by hypoxia plays a crucial role in the pathogenesis of PWMD [7]–[9]. Our previous studies have also shown that a strong and persistent inflammation occurred in the periventricular white matter (PWM) in hypoxic neonatal brain, which is closely associated with axonal disruption and pre-OLs injury [10], [11].…”

Section: Introductionmentioning

confidence: 99%

“…Amoeboid microglial cells (AMCs) are resident immune cells in the central nervous system (CNS) [16], [17]. Previous studies have demonstrated that AMCs were activated and released a large number of inflammatory cytokines and chemokines in the PWM at P1-7d after hypoxic exposure [10], [11], [16]. The number of activated microglial cells was markedly increased by migration of cells from blood or other brain regions, which would augment the inflammatory response occurring in the PWM of the hypoxic neonatal rats [16].…”

Section: Introductionmentioning

confidence: 99%

Astrocyte-Derived Proinflammatory Cytokines Induce Hypomyelination in the Periventricular White Matter in the Hypoxic Neonatal Brain

et al. 2014

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Hypoxic exposure in the perinatal period causes periventricular white matter damage (PWMD), a condition associated with myelination abnormalities. Under hypoxic conditions, glial cells were activated and released a large number of inflammatory mediators in the PWM in neonatal brain, which may result in oligodendrocyte (OL) loss and axonal injury. This study aims to determine if astrocytes are activated and generate proinflammatory cytokines that may be coupled with the oligodendroglial loss and hypomyelination observed in hypoxic PWMD. Twenty-four 1-day-old Wistar rats were exposed to hypoxia for 2 h. The rats were then allowed to recover under normoxic conditions for 7 or 28 days before being killed. Another group of 24 rats kept outside the chamber was used as age-matched controls. Upregulated expression of TNF-α and IL-1β was observed in astrocytes in the PWM of P7 hypoxic rats by double immunofluorescence, western blotting and real time RT-PCR. This was linked to apoptosis and enhanced expression of TNF-R1 and IL-1R1 in APC+ OLs. PLP expression was decreased significantly in the PWM of P28d hypoxic rats. The proportion of myelinated axons was markedly reduced by electron microscopy (EM) and the average g-ratios were higher in P28d hypoxic rats. Upregulated expression of TNF-α and IL-1β in primary cultured astrocytes as well as their corresponding receptors in primary culture APC+ oligodendrocytes were detected under hypoxic conditions. Our results suggest that following a hypoxic insult, astrocytes in the PWM of neonatal rats produce inflammatory cytokines such as TNF-α and IL-1β, which induce apoptosis of OLs via their corresponding receptors associated with them. This results in hypomyelination in the PWM of hypoxic rats.

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“…IL‐1β has been reported to reduce proliferation, differentiation and maturation of the OPCs (Vela et al, 2002) along with suppresion of axon development and growth (Han et al, 2017) resulting in hypomyelination (Xie et al, 2016). Activated microglia also promote protracted release of proinflammatory cytokines by astrocytes through macrophage colony‐stimulating factor in the periventricular white matter (Deng et al, 2010).…”

Section: Hypoxia Oligodendrocytes and Myelination Deficitsmentioning

confidence: 99%

Hypoxia and myelination deficits in the developing brain

Singh

Ling

Kaur

2018

Intl J of Devlp Neuroscience

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Myelination is a complex and orderly process during brain development that is essential for normal motor, cognitive and sensory functions. Cellular and molecular interactions between myelin-forming oligodendrocytes and axons are required for normal myelination in the developing brain. Oligodendrocyte progenitor cells (OPCs) proliferate and differentiate into mature myelin-forming oligodendrocytes. In this connection, astrocytes and microglia are also involved in survival and proliferation of OPCs. Hypoxic insults during the perinatal period affect the normal development, differentiation and maturation of the OPCs or cause their death resulting in impaired myelination. Several factors such as augmented release of proinflammatory cytokines by activated microglia and astrocytes, extracellular accumulation of excess glutamate and increased levels of nitric oxide are some of the underlying factors for hypoxia induced damage to the OPCs. Additionally, hypoxia also leads to down-regulation of several genes involved in oligodendrocyte differentiation encoding proteolipid protein, platelet-derived growth factor receptor and myelin-associated glycoprotein in the developing brain. Furthermore, oligodendrocytes may also accumulate increased amounts of iron in hypoxic conditions that triggers endoplasmic reticulum stress, misfolding of proteins and generation of reactive oxygen species that ultimately would lead to myelination deficits. More in-depth studies to elucidate the pathophysiological mechanisms underlying the inability of oligodendrocytes to myelinate the developing brain in hypoxic insults are desirable to develop new therapeutic options or strategies for myelination deficits.

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Microglia‐Derived Macrophage Colony Stimulating Factor Promotes Generation of Proinflammatory Cytokines by Astrocytes in the Periventricular White Matter in the Hypoxic Neonatal Brain

Cited by 34 publications

References 45 publications

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

Microglia-derived IL-1β contributes to axon development disorders and synaptic deficit through p38-MAPK signal pathway in septic neonatal rats

Astrocyte-Derived Proinflammatory Cytokines Induce Hypomyelination in the Periventricular White Matter in the Hypoxic Neonatal Brain

Hypoxia and myelination deficits in the developing brain

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