Neuroregenerative and protective functions of Leukemia Inhibitory Factor in perinatal hypoxic-ischemic brain injury

Lin, Jie; Niimi, Yusuke; Clausi, Mariano Guardia; Kanal, Hur Dolunay; Levison, Steven W.

doi:10.1016/j.expneurol.2020.113324

Cited by 18 publications

(19 citation statements)

References 57 publications

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“…It has been demonstrated in a neonatal mouse model of cerebral ischemia, CCL11 levels are also upregulated after cerebral ischemia, which results in promoting migration of NSPCs in these mice [ 99 , 100 ]. Another interesting cytokine was Leukemia Inhibitory Factor (LIF), where it has been shown in a neonatal mouse HI model, a reduction of astrogliosis and microgliosis after intranasal LIF administration, showing preservation of myelin [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Highlighted in red are the most significant cytokines expressed in both groups, while those cytokines present only in the LPS/HI condition were highlighted in yellow. For our study, the following 11 cytokines were used: proinflammatory M1: IL1-beta, IL-6, IL-12, iNOS, and TNF-alpha and anti-inflammatory M2: Arg-1, CD206, CCL11, IL-4, LIF, and TGF-beta) [47][48][49].…”

Section: 4mentioning

confidence: 99%

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Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Bernis

Schleehuber

Zweyer

et al. 2022

Oxidative Medicine and Cellular Longevity

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Hypoxic-ischemic encephalopathy (HIE) mainly affects preterm and term newborns, leading to a high risk of brain damage. Coexisting infection/inflammation and birth asphyxia are key factors associated with intracerebral increase of proinflammatory cytokines linked to HIE. Microglia are key mediators of inflammation during perinatal brain injury, characterized by their phenotypic plasticity, which may facilitate their participation in both the progression and resolution of injury-induced inflammation. The purpose of this study was to investigate the temporal expression of genes associated with pro- and anti-inflammatory cytokines as well as the nucleotide-binding domain, leucine-rich repeat protein (NLRP-3) inflammasome from microglia cells. For this purpose, we used our established neonatal rat model of inflammation-sensitized hypoxic-ischemic (HI) brain injury in seven-day-old rats. We assessed gene expression profiles of 11 cytokines and for NLRP-3 using real-time PCR from sorted CD11b/c microglia of brain samples at different time points (3.5 h after LPS injection and 0, 5, 24, 48, and 72 hours post HI) following different treatments: vehicle, E. coli lipopolysaccharide (LPS), vehicle/HI, and LPS/HI. Our results showed that microglia are early key mediators of the inflammatory response and exacerbate the inflammatory response following HI, polarizing into a predominant proinflammatory M1 phenotype in the early hours post HI. The brains only exposed to HI showed a delay in the expression of proinflammatory cytokines. We also demonstrated that NLRP-3 plays a role in the inflammatory resolution with a high expression after HI insult. The combination of both, a preinfection/inflammation condition and hypoxia-ischemia, resulted in a higher proinflammatory cytokine storm, highlighting the significant contribution of acute inflammation sensitizing prior to a hypoxic insult on the severity of perinatal brain damage.

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Section: Discussionmentioning

confidence: 99%

Section: 4mentioning

confidence: 99%

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Bernis

Schleehuber

Zweyer

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…The authors concluded that LIF was not exerting a direct action on the oligodendrocytes, but rather that LIF was increasing the production and release of IGF-1 from the macrophages, which was promoting the survival of the oligodendrocytes (Kerr & Patterson, 2005). By contrast, Lin et al, 2020, found that IGF-1 levels were higher in injured LIF Het mice after a neonatal hypoxia-ischemic brain injury, which is inconsistent with the proposed indirect actions of LIF through IGF-1 (Lin et al, 2020). Furthermore, arguing against an indirect mechanism, we used a PCR array to screen mRNAs for 85 growth factors and cytokines and did not find any that were differentially expressed by the injured LIF Het neocortex vs. the WT injured cortex (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…After intranasal administration, Lin et al, 2020 observed increased CC thickness and MBP staining in a model of perinatal hypoxia-ischemia. In that study, they evaluated BrdU incorporation into Olig2+ cells after intranasal LIF treatment and failed to show any differences between vehicle and LIF treated mice (Lin et al, 2020), leading them to conclude that intranasally administered LIF was exerting a strong survival promoting effect on the existing oligodendrocytes.…”

Section: Gliamentioning

confidence: 99%

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Frondelli

Mather

Levison

2020

Preprint

Self Cite

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Traumatic brain injury (TBI) is a significant problem that affects ∼500,000 children each year. As cell proliferation is disturbed by injury and is required for normal brain development, we investigated how a pediatric closed head injury (CHI) would affect the progenitors of the subventricular zone (SVZ). Additionally, we evaluated the contribution of Leukemia Inhibitory Factor (LIF) using LIF-heterozygous mice (LIF Het), as LIF is an injury-induced cytokine, known to influence neurogenesis and gliogenesis. CHI’s were performed on P20 LIF Het and WT mice. Ki-67 staining and stereology revealed that cell proliferation increased ∼250% in injured LIF Het mice compared to the 30% increase observed in injured WT mice at 48 h post CHI. Furthermore, Olig2+ cell proliferation increased in the SVZ and white matter of LIF Het injured mice at 48 h recovery. Using an 8-color flow cytometry panel, the proliferation of three distinct multipotential progenitors were greater in LIF Het injured mice compared to WT injured mice. Early oligodendrocyte progenitor cell (OPC) proliferation was 6-fold higher in LIF Het injured mice compared to WT injured mice. In vitro, addition of LIF decreased overall cell proliferation and OPC proliferation compared to controls. Addition of LIF to OPC cultures induced an increase of phospho-Akt after 20 minutes and an increase of phospho-S6RP at 20 and 40 minutes of exposure, suggesting that LIF stimulates the mammalian target of Rapamycin pathway. Altogether, our data provide new insights into the regulatory role of LIF in suppressing neural progenitor cell proliferation after a mild TBI.Main PointsOPC proliferation is dis-inhibited in LIF haplodeficient mice.LIF directly inhibits glial progenitor cell proliferation.LIF stimulates the mTOR pathway.

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“…All rats were placed in the testing room and familiarized with the surroundings before performing any behavioral tests. (1) At P17, we used the modified neurological severity score (mNSS) to detect the reflex, motor, sensory, and balance functions (Table 1) (Lin et al, 2020). ( 2) At P38, we performed the open field test to assess the distance traveled, time spent in exploring, and anxiety of rats.…”

Section: Behavioral Testingmentioning

confidence: 99%

Src Family Kinases Inhibition Ameliorates Hypoxic-Ischemic Brain Injury in Immature Rats

Qiu

Qian

et al. 2021

Front. Cell. Neurosci.

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Hypoxic-ischemic (HI) injury is one of the initial factors contributing to neonatal brain injury. Src family kinases (SFKs) are considered to act as molecular hubs for N-methyl-d-aspartate receptor (NMDAR) regulation and participate in the HI injury process. The objectives of this study were to evaluate the levels of phospho-Src (p-Src), the relationship between NMDARs and SFKs, and the effects of SFK inhibition on an immature rat HI brain injury model. The model was induced in 3-day-old Sprague–Dawley rats using the Rice-Vannucci model operation. The level of p-Src was evaluated using Western blotting. The association of NMDARs with SFKs was detected using Western blotting and coimmunoprecipitation. After intraperitoneal injection of 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3,4-d] pyrimidine (PP2), an SFK-selective inhibitor, neuropathological changes were observed by performing H&E and immunofluorescence staining, and the neurological functions were assessed using the following behavioral tests: modified neurological severity score, open field test, and Morris water maze test. The levels of p-Src first decreased at 0 h after injury, increased at 2 h after injury, and continuously decreased from 6 h to 3 days. Along with the increased p-Src levels observed at 2 h after injury, the phosphorylation of NMDAR subunit NR2B at tyrosine 1472 was increased. Following the administration of PP2, the increased p-Src and NMDAR-2B levels detected at 2 h after injury were decreased, and tissue injury and myelin basic protein expression were improved at 7 days after injury. The PP2 intervention improved the performance of injured rats on behavioral tests. In conclusion, we determined the patterns of p-Src expression after HI brain injury in immature rats and showed a relationship with the activated NMDA receptor. The inhibition of p-Src ameliorates neuropathological changes and damages neurological functions induced by HI injury.

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Neuroregenerative and protective functions of Leukemia Inhibitory Factor in perinatal hypoxic-ischemic brain injury

Cited by 18 publications

References 57 publications

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Temporal Characterization of Microglia-Associated Pro- and Anti-Inflammatory Genes in a Neonatal Inflammation-Sensitized Hypoxic-Ischemic Brain Injury Model

Oligodendrocyte progenitor proliferation is disinhibited following traumatic brain injury in LIF heterozygous mice

Src Family Kinases Inhibition Ameliorates Hypoxic-Ischemic Brain Injury in Immature Rats

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