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. 2019 Jan 23:692:1-9.
doi: 10.1016/j.neulet.2018.10.044. Epub 2018 Oct 24.

Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats

Brittany F Osborne  1 , Alexandra Turano  2 , Jasmine I Caulfield  3 , Jaclyn M Schwarz  4
Affiliations

Sex- and region-specific differences in microglia phenotype and characterization of the peripheral immune response following early-life infection in neonatal male and female rats

Brittany F Osborne et al. Neurosci Lett. .

Abstract

Early-life infection has been shown to have profound effects on the brain and behavior across the lifespan, a phenomenon termed "early-life programming". Indeed, many neuropsychiatric disorders begin or have their origins early in life and have been linked to early-life immune activation (e.g. autism, ADHD, and schizophrenia). Furthermore, many of these disorders show a robust sex bias, with males having a higher risk of developing early-onset neurodevelopmental disorders. The concept of early-life programming is now well established, however, it is still unclear how such effects are initiated and then maintained across time to produce such a phenomenon. To begin to address this question, we examined changes in microglia, the immune cells of the brain, and peripheral immune cells in the hours immediately following early-life infection in male and female rats. We found that males showed a significant decrease in BDNF expression and females showed a significant increase in IL-6 expression in the cerebellum following E.coli infection on postnatal day 4; however, for most cytokines examined in the brain and in the periphery we were unable to identify any sex differences in the immune response, at least at the time points examined. Instead, neonatal infection with E.coli increased the expression of a number of cytokines in the brain of both males and females similarly including TNF-α, IL-1β, and CD11b (a marker of microglia activation) in the hippocampus and, in the spleen, TNF-α and IL-1β. We also found that protein levels of GRO-KC, MIP-1a, MCP1, IP-10, TNF-α, and IL-10 were elevated 8-hours postinfection, but this response was resolved by 24-hours. Lastly, we found that males have more thin microglia than females on P5, however, neonatal infection had no effect on any of the microglia morphologies we examined. These data show that sex differences in the acute immune response to neonatal infection are likely gene, region, and even time dependent. Future research should consider these factors in order to develop a comprehensive understanding of the immune response in males and females as these changes are likely the initiating agents that lead to the long-term, and often sex-specific, effects of early-life infection.

Keywords: Cerebellum; Hippocampus; Microglia; Neonatal infection; Peripheral immune system; Sex differences.

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Figures

Figure 1.
Figure 1.. Impact of E.coli (1×106 CFU/0.1mL/kg) in the hippocampus of male and female neonates 8- and 24-hours following infection.
(A) Relative gene expression of the proinflammatory cytokine IL-1β is significantly increased in males and females following neonatal infection at both time points, and is significantly increased at 24 hours post-infection compared to 8 hours. (B) Relative gene expression of the proinflammatory cytokine IL-6 is not significantly different following neonatal infection at either time point in males or females. (C) Relative gene expression of the proinflammatory cytokine TNF-α is increased in males and females following neonatal infection at 8 hours, but not 24 hours post-infection. (D) Relative gene expression of a marker of microglial activation, CD11b, is significantly increased in males and females 8 hours post-infection but not at 24 hours. (E) Relative gene expression of Iba-1 is lower in males compared to females at 8 hours, but not at 24 hours post-infection. (F) Relative gene expression of the trophic factor, BDNF, is not significantly different following neonatal infection at either time point in males or females. Error bars represent ±SEM. *p < 0.05 represents the main effect of Neonatal Treatment. †p < 0.05 represents the main effect of Time. ϒp < 0.05 represents a significant interaction of Neonatal Treatment and Time. βp < 0.05 represents a significant interaction of Sex and Time.
Figure 2.
Figure 2.. Impact of E.coli (1×106 CFU/0.1mL/kg) in the cerebellum of male and female neonates 8- and 24-hours following infection.
(A) Relative gene expression of the proinflammatory cytokine IL-1β is not significantly different in males or females following neonatal infection at either time point. (B) Relative gene expression of the proinflammatory cytokine IL-6 is significantly increased in females 8 hours post-infection. (C) Relative gene expression of the proinflammatory cytokine TNF-α is not significantly different in males or females following neonatal infection at either time point. (D) Relative gene expression of a marker of microglial activation, CD11b, is significantly greater at 8 hours compared to 24 hours. (E) Relative gene expression of Iba-1 is lower in males compared to females at 8 hours, but not at 24 hours post-infection. (F) Relative gene expression of the trophic factor, BDNF, is significantly decreased in males following neonatal infection at 8 hours. Error bars represent ±SEM. †p < 0.05 represents the main effect of Time. βp < 0.05 represents a significant interaction of Sex and Time. ψp < 0.05 represents a significant interaction of Sex, Neonatal Treatment, and Time.
Figure 3.
Figure 3.. Impact of E.coli (1×106 CFU/0.1mL/kg) in the spleen of male and female neonates 8- and 24-hours following infection.
(A) Relative gene expression of the proinflammatory cytokine IL-1β is significantly increased in males and females following neonatal infection at both time points, but is significantly decreased at 24 hours post-infection compared to 8 hours. (B) Relative gene expression of the proinflammatory cytokine IL-6 is not significantly affected by neonatal infection and is significantly lower at 24 hours post-infection compared to 8 hours in males and females. (C) Relative gene expression of the proinflammatory cytokine TNF-α is increased in males and females following neonatal infection at both time points, but is significantly decreased at 24 hours post-infection compared to 8 hours. Error bars represent ±SEM. *p < .05 represents the main effect of Neonatal Treatment.†p < 0.05 represents the main effect of Time.
Figure 4.
Figure 4.. Impact of E.coli (1×106 CFU/0.1mL/kg) on peripheral immune response in the serum of male and female neonates 8- and 24-hours following infection.
(A) GRO-KC levels are significantly increased in males and females following neonatal infection at 8 hours post-infection, but levels are not detectable by 24 hours. (B) MIP-1a levels are significantly increased in males and females infected with E.coli 8 hours post-infection compared to 24 hours. (C) MCP1 levels are significantly increased in males and females infected with E.coli 8 hours post-infection compared to 24 hours. (D) IP-10 levels are significantly increased in males and females infected with E.coli 8 hours post-infection compared to 24 hours. (E) IL-1β levels are significantly higher 8 hours post-infection compared to 24 hours. (F) IL-6 levels were not detectable at 8 or 24 hours post-infection. (G) TNF-α levels are significantly increased in males and females infected with E.coli 8 hours post-infection compared to 24 hours. (H) IL-10 levels are significantly increased in males and females infected with E.coli 8 hours post-infection compared to 24 hours. Error bars represent ±SEM. *p < 0.05 represents the main effect of Neonatal Treatment. †p < 0.05 represents the main effect of Time. ϒp < 0.05 represents a significant interaction of Neonatal Treatment and Time.
Figure 5.
Figure 5.. Microglia Counts in the hippocampus 24-hours Post Infection.
(A) Representative images of the four microglial phenotypes (round, stout, thick, thin) found in the hippocampus on P5 (B) There are no significant differences in microglia number in the whole hippocampus 24-hours post infection. (C) Males have significantly more thin microglia than females in the CA1 region on P5. (D) There are no significant differences in microglia number in the CA3 region 24-hours post infection. (E) There are no significant differences in microglia number in the dentate gyrus 24-hours post infection. (F) There are significantly more stout microglia in the hippocampus on P5 relative to all other microglial morphologies. Error bars represent ±SEM. *p < 0.05.
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