An examination of changes in maternal neuroimmune function during pregnancy and the postpartum period

Abstract

There is strong evidence that the immune system changes dramatically during pregnancy in order to prevent the developing fetus from being "attacked" by the maternal immune system. Due to these alterations in peripheral immune function, many women that suffer from autoimmune disorders actually find significant relief from their symptoms throughout pregnancy; however, these changes can also leave the mother more susceptible to infections that would otherwise be mitigated by the inflammatory response (Robinson and Klein, 2012). Only one other study has looked at changes in microglial number and morphology during pregnancy and the postpartum period (Haim et al., 2016), but no one has yet examined the neuroimmune response following an immune challenge during this time. Therefore, in this study, we investigated the impact of an immune challenge during various time-points throughout pregnancy and the postpartum period on the expression of immune molecules in the brain of the mother and fetus. Our results indicate that similar to the peripheral immune suppression measured during pregnancy, we also see significant suppression of the immune response in the maternal brain, particularly during late gestation. In contrast to the peripheral immune system, immune modulation in the maternal brain extends moderately into the postpartum period. Additionally, we found that the fetal immune response in the brain and placenta is also suppressed just before parturition, suggesting that cytokine production in the fetus and placenta are mirroring the peripheral cytokine response of the mother.

Keywords: Hormones; Immune function; Microglia; Mood and anxiety disorders; Peripartum depression; Pregnancy.

Fig. 1.

Examination of cytokine expression in maternal spleen at various time-points throughout pregnancy and the postpartum period. There is a significant interaction of pregnancy condition and LPS treatment for the expression of IL-1β, IL-6, and IFNγ in the spleen (Treatment × Condition: IL-1β: F_5,84 = 3.22; p = 0.010, IL-6: F_5,84 = 2.34; p = 0.048, IFNγ: F_5,84 = 2.32; p = 0.050; ABC). The expression of both IL-β and IL-6 were significantly attenuated in LPS-treated females at E11 compared to the expression of these same genes in LPS-treated non-pregnant females (IL-1β: p < 0.001; IL-6: p < 0.001; AB). This attenuation was also apparent at E22 for IL-β, IL-6, and IFNγ (IL-1β: p < 0.001; IL-6: p < 0.001, IFNγ: p < 0.001; ABC). The expression of IL-1β and IFNγ immediately returned to pre-pregnancy levels on the day of parturition (P0) as the expression levels of these cytokines in the spleen were not significantly different from non-pregnant females treated with LPS (IL-1β: p = 0.114, IFNγ: p = 0.441; AC). There was a main effect of pregnancy condition and LPS treatment for the expression of IL-4 in the spleen where non-pregnant controls are significantly different than E11 and E22 time-points (Condition: F_5,81 = 4.465; p = 0.001, Treatment: F_1,81 = 4.293; p = 0.041; D). There was also a significant interaction of pregnancy condition and LPS treatment for the expression of TLR4 (Treatment × Condition: TLR4: F_5,84 = 3.15; p = 0.012; Fig. 1E), such that LPS-treated females at E11, E22, P0, and P2 had a significantly attenuated response compared to the LPS-treated non-pregnant females. n = 7–8 rats per group. Condition × Treatment interaction: groups that do not share any capital letters are considered significantly significant (p < 0.05). Main effect of Condition: groups that do not share any lowercase letters are considered statistically significant (p < 0.05). Main effect of Treatment: groups with an asterisk are considered statistically significant (p < 0.05).

Fig. 2.

Examination of cytokine expression in maternal hypothalamus/preoptic area at various time-points throughout pregnancy and the postpartum period. There was a significant treatment by condition interaction in the expression of IL-1β, IL-6, and CD11b (IL-1β: F_5,82 = 2.614, p = 0.030; IL-6: F_5,82 = 2.822; p = 0.021; CD11b: F_5,82 = 2.368; p = 0.047; ABC). Specifically, IL-1β gene expression following the LPS challenge in the HyPoA is significantly attenuated during pregnancy at both E11, E22, P0, and P9 compared to non-pregnant controls (E11: p = 0.038; E22: p = 0.001; P0: p = 0.005; P9: p = 0.002; A). IL-6 gene expression is attenuated following LPS treatment at E11, P2, and P9 compared to non-pregnant controls (E11: p = 0.008, P0: p = 0.001, P9: p = 0.001; B). There was a significant attenuation in CD11b gene expression following LPS during postpartum days P0 and P9 compared to LPS treated animals on day E22 (P0: p = 0.023, P9: 0.038; C). n = 7–8 rats per group. Condition × Treatment interaction: groups that do not share any capital letters are considered significantly significant (p < 0.05).

Fig. 3.

Examination of cytokine expression in maternal hippocampus at various time-points throughout pregnancy and the postpartum period. There was a significant treatment by condition interaction for IL-1β gene expression following LPS exposure where time-points E22 and P0 were significantly different than non-pregnant controls (IL-1β: F_5,81 = 3.685; p = 0.005; A). There was a main effect of both condition and treatment for IL-6 expression where time-points E11, E22, and P0 were significantly different than non-pregnant controls (E11: p = 0.023; E22: p = 0.040; P0: p = 0.030; B). There was also a main effect of treatment for CD11b expression, where CD11b expression is generally increased following LPS treatment (F_1,83 = 9.661; p = 0.021; C). n = 7–8 rats per group. Condition × Treatment interaction: groups that do not share any capital letters are considered significantly significant (p < 0.05). Main effect of Condition: groups that do not share any lowercase letters are considered statistically significant (p < 0.05). Main effect of Treatment: groups with an asterisk are considered statistically significant (p < 0.05).

Fig. 4.

Examination of cytokine expression in maternal medial prefrontal cortex at various time-points throughout pregnancy and the postpartum period. There was a treatment by condition interaction for IL-1β gene expression (F_5,80 = 2.668; p = 0.028) where LPS-induced IL-1β expression was significantly attenuated at E22 compared to non-pregnant controls (E22: p = 0.002; A). There was a main effect of condition and treatment for IL-6 gene expression where E11 pregnancy time-point was significantly different than non-pregnant controls (Condition: F_5,78 = 2.550; p = 0.034, Treatment: F_1,78 = 26.209; p < 0.001; B). There was also a main effect of condition for CD11b where E11, P0, and P9 were significantly different than non-pregnant controls (F_5,79 = 3.144; p = 0.012; C). We found a main effect of condition for BDNF where E11 expression is significantly decreased compared to the non-pregnant group and that E22 is significantly increased compared to all other time-points with the exception of the non-pregnant group (F_5,79 = 8.451; p = < 0.001; D). There was a main effect in TLR4 expression where P0 was significantly suppressed compared to the non-pregnant group, and E22 gene expression was significantly higher in E11, P0, and P9 (F_5,80 = 5.608; p = < 0.001; E). n = 7–8 rats per group. Condition × Treatment interaction: groups that do not share any capital letters are considered significantly significant (p < 0.05). Main effect of Condition: groups that do not share any lowercase letters are considered statistically significant (p < 0.05). Main effect of Treatment: groups with an asterisk are considered statistically significant (p < 0.05).

Fig. 5.

Examination of cytokine expression in fetal head and placenta at embryonic day 11 (E11) and embryonic day 22 (E22). There was a significant treatment by condition interaction for IL-1β expression (F_1,46 = 36.067; p < 0.001; A) as well as IL-6 expression (F_1,45 = 18.225; p < 0.001; B) where gene expression was significantly higher in E11 pups compared to saline treated controls but also compared to E22 pups following LPS administration (p < 0.05). There was a main effect of condition in CD11b gene expression where E22 pups showed significantly higher gene expression compared to E11 pups (F_1,46 = 131.846 p < 0.001; C). Similar to fetal brain, there was a significant treatment by condition interaction for IL-1β gene expression (F_1,46 = 25.705; p < 0.001; D) and IL-6 expression (F_1,46 = 13.472; p = 0.001; E), where inflammatory gene expression was significantly higher in placentas collected at E11 compared to placentas taken at E22 following maternal LPS administration. There were no significant differences between the sexes in the immune response seen in the placenta. *p < 0.05. n = 5–8 rats per group. Condition × Treatment interaction: groups that do not share any capital letters are considered significantly significant (p < 0.05). Main effect of Condition: groups that do not share any lowercase letters are considered statistically significant (p < 0.05).