Maternal nematode infection upregulates expression of Th2/Treg and diapedesis related genes in the neonatal brain

Abstract

Intestinal nematode infections common during pregnancy have recently been shown to have impacts that extend to their uninfected offspring including altered brain gene expression. If maternal immune signals reach the neonatal brain, they might alter neuroimmune development. We explored expression of genes associated with four distinct types of T cells (Th1, Th2, Th17, Treg) and with leukocyte transendothelial migration and endocytosis transport across the blood–brain barrier (BBB) in the postnatal brain of offspring of nematode-infected mice, through secondary analysis of a whole brain gene expression database. Th1/Th17 expression was lowered by maternal infection as evidenced by down-regulated expression of IL1β, Th1 receptors and related proteins, and of IL22 and several Th17 genes associated with immunopathology. In contrast, Th2/Treg related pathways were upregulated as shown by higher expression of IL4 and TGF-β family genes. Maternal infection also upregulated expression of pathways and integrin genes involved in transport of leukocytes in between endothelial cells but downregulated endosome vesicle formation related genes that are necessary for endocytosis of immunoglobulins across the BBB. Taken together, pup brain gene expression indicates that maternal nematode infection enhanced movement of leukocytes across the neonatal BBB and promoted a Th2/Treg environment that presumably minimizes the proinflammatory Th1 response in the pup brain.

Maternal gastrointestinal nematode infection enhances spatial memory of uninfected juvenile mouse pups

“…One possibility is that the Th2/Treg immune response in the infected dam 75 induces a similar systemic response in the uninfected pup that extends to and alters the immune profile in the pup brain. Consistent with this, maternal H. bakeri infection up-regulated expression of Th2/Treg pathways and their associated cytokines including interleukin (IL)-4 and transforming growth factor-β (TGF-β) in the PD 7 pup brain, while down-regulating Th1 pathways and the inflammatory cytokine IL-1β 48 , 76 . Elevated IL-1β has been shown to impair spatial memory 77 , and knock-out studies have highlighted the beneficial and critical importance of IL-4 for the formation and retention of spatial memories 78 , 79 .…”

“…IL-4 stimulates astrocytes to produce brain-derived neurotrophic factor (BDNF) 78 , a key molecule for regulating cognitive processes, including LTP and neurogenesis 80 , 81 . Of note, in addition to up-regulating IL-4 expression 48 , 76 , maternal H. bakeri infection also up-regulated BDNF expression in the brains of PD 7 neonates (unpublished data). Therefore we hypothesize that the enhanced spatial memory in the pups of infected dams is associated with a regulatory Th2/Treg neuroimmune environment which promotes LTP and neurogenesis via the production of BDNF by astrocytes.…”

Gastrointestinal nematode infection during pregnancy and lactation enhances spatial reference memory and reduces indicators of anxiety-like behaviour in uninfected adult female mouse offspring

“…The ability of the female sex hormones, estrogen and progesterone, to dampen Th1 immunity (Roved et al, 2017) may offer protection to female offspring in these models, by ameliorating the damaging neuroinflammatory responses. In contrast to LPS and Polyl:C models, maternal H. bakeri infection induces a Th2/Treg, not a Th1, immune response in the mother (Odiere et al, 2013;Su et al, 2023), which is mimicked in the brain of neonatal and juvenile offspring and is suggested to promote hippocampal BDNF, neurogenesis, LTP and spatial memory (Haque et al, 2019;El Ahdab et al, 2021;Noel et al, 2024). Given that estrogen and progesterone enhance Th2 immune responses (Roved et al, 2017), it is possible that the influence of these sex hormones on the immune system may allow the Th2/Treg biased neuroimmune environment to persist in adult female offspring of H. bakeri dams, explaining the positive influence on female behaviour at adulthood.…”

“…Interestingly, however, it was observed that maternal exposure to the immunoregulatory gastrointestinal (GI) nematode, Heligmosomoides bakeri (also referred to as Heligmosomoides polygyrus and previously known as Nematospiroides dubius), may actually benefit, not harm, at least some aspects of brain development of the offspring (Haque et al, 2019;El Ahdab et al, 2021;Noel et al, 2022;Noel et al, 2024). In contrast to the type 1 pro-inflammatory immune responses (e.g.…”

“…Furthermore, maternal H. bakeri infection resulted in a Th2/Treg biased neuroimmune environment in the uninfected offspring. Gene expression analysis of the brains of neonates of infected dams revealed up-regulated Th2/Treg pathways, including the genes for the potent immunoregulatory cytokines IL-4 and TGF-β, and down-regulated Th1/Th17 pathways (Haque et al, 2019;El Ahdab et al, 2021), mimicking the immune response of the infected mother (Odiere et al, 2013;Su et al, 2023). This altered neuroimmune environment was also seen in the hippocampus of male and female three-week old juvenile offspring where the immunoregulatory TGF-β signaling pathway was up-regulated, and where a greater number of two immune sensitive cells, microglia and astrocytes, were observed, as well as a higher percentage of CD206 positive microglia (Noel et al, 2024) which are typically increased in response to the Th2 cytokine, IL-4 (Francos-Quijorna et al, 2016;Liu et al, 2016;Jurga et al, 2020;Zhang et al, 2021).…”