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Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy.

Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F - J Neuroinflammation (2015)

Bottom Line: However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE.Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE.Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. memirza@uchc.edu.

ABSTRACT

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insults and suffer more long-term deficits than females; however, the mechanisms underlying this sex difference remain elusive. Inflammatory processes initiated by microglial activation are fundamental in the pathophysiology of ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in the neonatal brain under normal conditions. How these basal sex differences in microglia affect HIE remains largely unexplored. This study investigated sex differences in ischemic outcomes and inflammation triggered by HIE. We hypothesize that ischemia induces sex-specific brain injury in male and female neonates and that microglial activation and inflammatory responses play an important role in this sexual dimorphism.

Methods: Male and female C57BL6 mice were subjected to 60-min Rice-Vanucci modeling (RVM) at post-natal day 10 (P10) to induce HIE. Stroke outcomes were measured 1, 3, 7, and 30 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry and cytokine analysis.

Results: On day 1 of HIE, no difference in infarct volumes or seizure scores was seen between male and female neonates. However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE. Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE. Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

Conclusions: HIE leads to an equivalent primary brain injury in male and female neonates at the acute stage that develops into sexually dimorphic outcomes at later time points. An innate immune response secondary to the primary injury may contribute to sexual dimorphism in HIE.

No MeSH data available.


Related in: MedlinePlus

Infiltration of peripheral leukocytes in the ipsilateral hemispheres at 3 days of HIE. (A) Analysis of gated peripheral myeloid cells. Q1 quadrant: monocytes; Q2 quadrant: neutrophils. (B, C, D, E) Quantification of total peripheral myeloid cells, monocytes, neutrophils, and lymphocytes in HIE brains. *P < .05.
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Fig4: Infiltration of peripheral leukocytes in the ipsilateral hemispheres at 3 days of HIE. (A) Analysis of gated peripheral myeloid cells. Q1 quadrant: monocytes; Q2 quadrant: neutrophils. (B, C, D, E) Quantification of total peripheral myeloid cells, monocytes, neutrophils, and lymphocytes in HIE brains. *P < .05.

Mentions: Inflammatory responses involve activation of resident immune cells (microglia) and infiltration of peripheral leukocytes in the ischemic brain. To examine the infiltrating leukocytes with flow cytometry, we gated monocytes as CD45highCD11b+Ly6C+Ly6G−, neutrophils as CD45highCD11b+Ly6G+, total peripheral myeloid cells as CD45highCD11b+, and lymphocytes as CD45highCD11b− (Figures 3A and 4A). There were significantly more monocyte and lymphocyte infiltration in male vs. female brains 3 days after HIE (Figure 4A, C, E). Peripheral total myeloid cells and neutrophils also showed a trend towards increased levels in male brains, but this did not reach significance (Figure 4A, B, D). No sex differences in infiltration of peripheral leukocytes were seen at 1 day of HIE (data not shown).Figure 4


Sexually dimorphic outcomes and inflammatory responses in hypoxic-ischemic encephalopathy.

Mirza MA, Ritzel R, Xu Y, McCullough LD, Liu F - J Neuroinflammation (2015)

Infiltration of peripheral leukocytes in the ipsilateral hemispheres at 3 days of HIE. (A) Analysis of gated peripheral myeloid cells. Q1 quadrant: monocytes; Q2 quadrant: neutrophils. (B, C, D, E) Quantification of total peripheral myeloid cells, monocytes, neutrophils, and lymphocytes in HIE brains. *P < .05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4359482&req=5

Fig4: Infiltration of peripheral leukocytes in the ipsilateral hemispheres at 3 days of HIE. (A) Analysis of gated peripheral myeloid cells. Q1 quadrant: monocytes; Q2 quadrant: neutrophils. (B, C, D, E) Quantification of total peripheral myeloid cells, monocytes, neutrophils, and lymphocytes in HIE brains. *P < .05.
Mentions: Inflammatory responses involve activation of resident immune cells (microglia) and infiltration of peripheral leukocytes in the ischemic brain. To examine the infiltrating leukocytes with flow cytometry, we gated monocytes as CD45highCD11b+Ly6C+Ly6G−, neutrophils as CD45highCD11b+Ly6G+, total peripheral myeloid cells as CD45highCD11b+, and lymphocytes as CD45highCD11b− (Figures 3A and 4A). There were significantly more monocyte and lymphocyte infiltration in male vs. female brains 3 days after HIE (Figure 4A, C, E). Peripheral total myeloid cells and neutrophils also showed a trend towards increased levels in male brains, but this did not reach significance (Figure 4A, B, D). No sex differences in infiltration of peripheral leukocytes were seen at 1 day of HIE (data not shown).Figure 4

Bottom Line: However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE.Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE.Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT, 06030, USA. memirza@uchc.edu.

ABSTRACT

Background: Neonatal hypoxic-ischemic encephalopathy (HIE) is an important cause of motor and cognitive impairment in children. Clinically, male infants are more vulnerable to ischemic insults and suffer more long-term deficits than females; however, the mechanisms underlying this sex difference remain elusive. Inflammatory processes initiated by microglial activation are fundamental in the pathophysiology of ischemia. Recent studies report a sexual dimorphism in microglia numbers and expression of activation markers in the neonatal brain under normal conditions. How these basal sex differences in microglia affect HIE remains largely unexplored. This study investigated sex differences in ischemic outcomes and inflammation triggered by HIE. We hypothesize that ischemia induces sex-specific brain injury in male and female neonates and that microglial activation and inflammatory responses play an important role in this sexual dimorphism.

Methods: Male and female C57BL6 mice were subjected to 60-min Rice-Vanucci modeling (RVM) at post-natal day 10 (P10) to induce HIE. Stroke outcomes were measured 1, 3, 7, and 30 days after stroke. Microglial activation and inflammatory responses were evaluated by flow cytometry and cytokine analysis.

Results: On day 1 of HIE, no difference in infarct volumes or seizure scores was seen between male and female neonates. However, female neonates exhibited significantly smaller infarct size and fewer seizures compared to males 3 days after HIE. Females also had less brain tissue loss and behavioral deficits compared to males at the chronic stage of HIE. Male animals demonstrated increased microglial activation and up-regulated inflammatory response compared to females at day 3.

Conclusions: HIE leads to an equivalent primary brain injury in male and female neonates at the acute stage that develops into sexually dimorphic outcomes at later time points. An innate immune response secondary to the primary injury may contribute to sexual dimorphism in HIE.

No MeSH data available.


Related in: MedlinePlus