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Sex differences in preterm cytokine and inflammasome responses and modulation by exogenous sex steroids
Matthew McGovern1,2,3, Lynne A Kelly4,5, Rebecca Finnegan1
1Discipline of Paediatrics, Trinity College, the University of Dublin, Dublin, Ireland.
Insights
Female sex hormones reduce inflammatory responses in preterm infants, suggesting a role in the female immune advantage. Term infants show a more robust inflammatory profile than preterm infants.
Area of Science:
- Neonatal immunology
- Inflammasome biology
- Sex differences in immunity
Background:
- Preterm infants face higher sepsis risk due to immature immune systems.
- Neonatal immune cells exhibit distinct cytokine responses influenced by sex.
- Inflammasome activation and cytokine profiles vary between preterm and term neonates.
Purpose of the Study:
- To investigate inflammasome activation and cytokine responses to endotoxin and sex hormones in preterm and term neonates.
- To determine sex-specific differences in immune responses in neonates.
- To explore the impact of sex hormones on neonatal inflammatory pathways.
Main Methods:
- Peripheral blood samples from preterm (n=40) and term (n=32) neonates were stimulated with Lipopolysaccharide (LPS), Estradiol (E2), Progesterone (Pg), or Pam3CSK4.
- Biomarkers were analyzed using ELISA.
- Inflammasome gene expression (NLRP3, ASC, IL1-β, AIM2) was quantified via Taqman RT-PCR.
Main Results:
- Female sex hormones, particularly estradiol, reduced Interleukin-1 beta (IL-1β) expression, with a pronounced effect in preterm infants.
- Female preterm infants showed a greater response to progesterone's anti-inflammatory effects compared to males.
- Term neonates exhibited higher IL-1β, IL-18, and IL-1RA expression than preterm infants.
- Estradiol and progesterone decreased cytokine expression in preterm infants, while inflammasome gene expression did not differ between sexes.
Conclusions:
- Sex hormones significantly modulate neonatal cytokine expression, with distinct responses observed between sexes.
- Gestation impacts inflammatory response, with term infants displaying a more robust profile and preterm infants showing heightened responsiveness to hormonal stimuli.
- Female sex hormones contribute to immune modulation in neonates, potentially explaining the observed female immune advantage in sepsis outcomes.
Background:
Preterm infants are at increased risk of sepsis compared to adults and older children. Preterm immune cells have altered cytokine responses compared to term neonates and adults and all have sex-related differences in immunity. We examined inflammasome activation and cytokines with endotoxin and sex steroid hormones between preterm and term neonates.
Methods:
Preterm (n = 40) and term (n = 32) peripheral blood samples were incubated with Lipopolysaccharide (LPS), Estradiol (E2), Progesterone (Pg) or Pam3CSK4 and biomarkers were analysed by ELISA. Inflammasome genes, NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC), Interleukin-1 beta (IL1-β) and Absent In Melanoma 2 (AIM 2) were analysed with Taqman RT-PCR.
Results:
IL-1β cytokine expression was reduced by female sex hormones and notably the effect of estradiol was greatest in the preterm population. Female preterm neonates were more responsive to the anti-inflammatory effect of progesterone than male preterm infants. Term neonates had higher IL-1β, IL-18 and IL-1RA expression than preterm infants. Overall, in preterms, E2 and Pg lowered cytokine expression levels. Inflammasome gene expression profiles did not differ between preterm male and female neonates.
Conclusion:
Sex hormones altered the expression of multiple cytokines, and cytokine responses differ by sex. Gestation plays an important role in the inflammatory response, and we note term infants have a more robust profile while preterm infants are more responsive to hormonal stimulus. Female sex hormones have an important role in modulating neonatal immune response and may contribute to the female immune advantage.
Impact:
Female sex hormones play an important role in modulating the neonatal immune response. This is reflected clinically by better bacterial clearance and improved sepsis outcome in females. This study aims to test the hypothesis that male and female neonates differ in their cytokine and inflammasome response and in response to endotoxin and sex steroid hormones. In preterm infants there is a sex difference in IL-1b responses which is observed rapidly following endotoxin stimulation. Differing immune responses according to sex has implications for future clinical application. Further work to characterise these sex differences may help in guiding therapy during sepsis.
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