CXCR2 Blockade Mitigates Neural Cell Injury Following Preclinical Chorioamnionitis

Yellowhair, Tracylyn R.; Newville, Jessie; Noor, Shahani; Maxwell, Jessie R.; Milligan, Erin D.; Robinson, Shenandoah; Jantzie, Lauren L.

doi:10.3389/fphys.2019.00324

Cited by 28 publications

(33 citation statements)

References 96 publications

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“…In the presence of neuroinflammation, CXCL1 and CXCR2 are upregulated rapidly ( Carlson et al, 2008 ; Kerstetter et al, 2009 ; Kielian et al, 2001 ; Liu et al, 2010 ; Roy et al, 2012 ). Studies in neonatal brain injury and in adult neurodegenerative disorders have shown that inhibiting the CXCR2 receptor is neuroprotective and can attenuate white matter and axonal injury ( Yellowhair et al, 2019 ). This neuroprotective effect is felt to be related to a decrease in neutrophil infiltration in the brain ( Yellowhair et al, 2018 , 2019 ) which is often a secondary response following injury and can exacerbate the initial injury.…”

Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Arteaga

Zhang

Khoury

et al. 2021

Neurobiology of Disease

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The result of a deprivation of oxygen and glucose to the brain, hypoxic–ischemic encephalopathy (HIE), remains the most common cause of death and disability in human neonates globally and is mediated by glutamate toxicity and inflammation. We have previously shown that the enzyme glutamate carboxypeptidase (GCPII) is overexpressed in activated microglia in the presence of inflammation in fetal/newborn rabbit brain. We assessed the therapeutic utility of a GCPII enzyme inhibitor called 2-(3-Mercaptopropyl) pentanedioic acid (2MPPA) attached to a dendrimer (D-2MPPA), in order to target activated microglia in an experimental neonatal hypoxia-ischemia (HI) model using superoxide dismutase transgenic (SOD) mice that are often more injured after hypoxia-ischemia than wildtype animals. SOD overexpressing and wild type (WT) mice underwent permanent ligation of the left common carotid artery followed by 50 min of asphyxiation (10% O 2 ) to induce HI injury on postnatal day 9 (P9). Cy5-labeled dendrimers were administered to the mice at 6 h, 24 h or 72 h after HI and brains were evaluated by immunoflu orescence analysis 24 h after the injection to visualize microglial localization and uptake over time. Expression of GCPII enzyme was analyzed in microglia 24 h after the HI injury. The expression of pro- and anti-inflammatory cytokines were analyzed 24 h and 72 h post-HI. Brain damage was analyzed histologically 7 days post-HI in the three randomly assigned groups: control (C); hypoxic-ischemic (HI); and HI mice who received a single dose of D-2MPPA 6 h post-HI (HI+D-2MPPA). First, we found that GCPII was overexpressed in activated microglia 24 h after HI in the SOD overexpressing mice. Also, there was an increase in microglial activation 24 h after HI in the ipsilateral hippocampus which was most visible in the SOD+HI group. Dendrimers were mostly taken up by microglia by 24 h post-HI; uptake was more prominent in the SOD+HI mice than in the WT+HI. The inflammatory profile showed significant increase in expression of KC/GRO following injury in SOD mice compared to WT at 24 and 72 h. A greater and significant decrease in KC/GRO was seen in the SOD mice following treatment with D-2MPPA. Seven days after HI, D-2MPPA treatment decreased brain injury in the SOD+HI group, but not in WT+HI. This reduced damage was mainly seen in hippocampus and cortex. Our data indicate that the best time point to administer D-2MPPA is 6 h post-HI in order to suppress the expression of GCPII by 24 h after the damage since dendrimer localization in microglia is seen as early as 6 h with the peak of GCPII upregulation in activated microglia seen at 24 h post-HI. Ultimately, treatment with D-2MPPA

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Section: Discussionmentioning

confidence: 99%

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Arteaga

Zhang

Khoury

et al. 2021

Neurobiology of Disease

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“…By Multiplex and immunohistochemistry analysis, we were able to show that highly activated factors in APOE4 injured mice include CXCL1, Il-6, TNF-α, and microglia. CXCL1 is a cytokine that is a ligand for the CXCR2 receptor, whose activation has been implicated in increased pain after injury 77 and blockade has been shown to reduce neuroinflammation after injury 78 . Il-6 is an important pro-inflammatory interleukin.…”

Section: Discussionmentioning

confidence: 99%

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes

Giarratana

Zheng

Reddi

et al. 2020

Sci Rep

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After traumatic brain injury (TBI), some people have worse recovery than others. Single nucleotide polymorphisms (SNPs) in Apolipoprotein E (APOE) are known to increase risk for developing Alzheimer’s disease, however there is controversy from human and rodent studies as to whether ApoE4 is a risk factor for worse outcomes after brain trauma. To resolve these conflicting studies we have explored the effect of the human APOE4 gene in a reproducible mouse model that mimics common human injuries. We have investigated cellular and behavioral outcomes in genetically engineered human APOE targeted replacement (TR) mice following repeated mild TBI (rmTBI) using a lateral fluid percussion injury model. Relative to injured APOE3 TR mice, injured APOE4 TR mice had more inflammation, neurodegeneration, apoptosis, p-tau, and activated microglia and less total brain-derived neurotrophic factor (BDNF) in the cortex and/or hippocampus at 1 and/or 21 days post-injury. We utilized a novel personalized approach to treating APOE4 susceptible mice by administering Bryostatin-1, which improved cellular as well as motor and cognitive behavior outcomes at 1 DPI in the APOE4 injured mice. This study demonstrates that APOE4 is a risk factor for poor outcomes after rmTBI and highlights how personalized therapeutics can be a powerful treatment option.

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“…Ystgaard et al found different distribution of NLRP3 gene upregulation in their newborn mouse model 24 h post hypoxic-ischemic injury, with a significant upregulation in the hippocampus and thalamus ( 35 ). Yellowhair et al showed that CXCL1/CXCR2 signaling contributes to newborn brain inflammation in an in-vitro model of preclinical chorioamnionitis and that blocking the CXCR2 receptor reduces neuroinflammation in different white matter regions ( 36 ). Interestingly in our study, we found a gender-specific upregulation of CXCL1 protein level in males in the LPS/HI group compared with the Sham group in the cortex ( Figure 4 ).…”

Section: Discussionmentioning

confidence: 99%

Involvement of CXCL1/CXCR2 During Microglia Activation Following Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Rats

et al. 2020

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Background: Microglia are key mediators of inflammation during perinatal brain injury. As shown experimentally after inflammation-sensitized hypoxic ischemic (HI) brain injury, microglia are activated into a pro-inflammatory status 24 h after HI involving the NLRP3 inflammasome pathway. The chemokine (C-X-C motif) ligand 1 (CXCL1), and its cognate receptor, CXCR2, have been shown to be involved in NLRP3 activation, although their specific role during perinatal brain injury remains unclear. In this study we investigated the involvement of CXCL1/CXCR2 in brain tissue and microglia and brain tissue after inflammation-sensitized HI brain injury of newborn rats. Methods: Seven-day old Wistar rat pups were either injected with vehicle (NaCl 0.9%) or E. coli lipopolysaccharide (LPS), followed by left carotid ligation combined with global hypoxia (8% O 2 for 50 min). Pups were randomized into four different treatment groups: (1) Sham group ( n = 21), (2) LPS only group ( n = 20), (3) Veh/HI group ( n = 39), and (4) LPS/HI group ( n = 42). Twenty-four hours post hypoxia transcriptome and gene expression analysis were performed on ex vivo isolated microglia cells in our model. Additionally protein expression was analyzed in different brain regions at the same time point. Results: Transcriptome analyses showed a significant microglial upregulation of the chemokine CXCL1 and its receptor CXCR2 in the LPS/HI group compared with the other groups. Gene expression analysis showed a significant upregulation of CXCL1 and NLRP3 in microglia cells after inflammation-sensitized hypoxic-ischemic brain injury. Additionally, protein expression of CXCL1 was significantly upregulated in cortex of male pups from the LPS/HI group. Conclusion: These results indicate that the CXCL1/CXCR2 pathway may be involved during pro-inflammatory microglia activation following inflammation-sensitized hypoxic-ischemic brain injury in neonatal rats. This may lead to new treatment options altering CXCR2 activation early after HI brain injury.

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CXCR2 Blockade Mitigates Neural Cell Injury Following Preclinical Chorioamnionitis

Cited by 28 publications

References 96 publications

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

Neuroprotective effects of a dendrimer-based glutamate carboxypeptidase inhibitor on superoxide dismutase transgenic mice after neonatal hypoxic-ischemic brain injury

APOE4 genetic polymorphism results in impaired recovery in a repeated mild traumatic brain injury model and treatment with Bryostatin-1 improves outcomes

Involvement of CXCL1/CXCR2 During Microglia Activation Following Inflammation-Sensitized Hypoxic-Ischemic Brain Injury in Neonatal Rats

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