Over the past years, multiple studies have analyzed the possible fetal programming effects of maternal infection and MIA on the offspring’s immune system. In MIA exposed offspring, alterations were found in cytokine profiles (Table 1 and online dataset), immune profiles, and immune cell function (Table 2). Most studies using preclinical MIA models concentrate on the association between MIA and neurodevelopmental disorders such as schizophrenia and autism spectrum disorder. Unsurprisingly, acute and long-term alterations of immune function have been studied in the offspring’s brain. Numerous studies have analyzed the cytokine profile in the brain of the offspring at various ages and brain regions (Table 1 and online dataset).

Table 1 Cytokine profile of MIA exposed offspring. Reported alterations in cytokine profile in different tissues or produced after in vitro stimulation from multiple studies. Cytokines reported were altered at specific age, with or without immune induction or at a specific part of the brain. A complete overview of the cytokine profile, including unaltered cytokines, can be found in the and online dataset. GD; gestational day, PND; postnatal dayTable 2 Immune cell profile and immune function alterations observed in MIA exposed offspring. Reported alterations in the immune cell profile and immune function in different cell populations or after postnatal secondary hit from multiple studies. GD; gestational day, PND; postnatal day, EAE; experimental autoimmune encephalomyelitisEffect of MIA on the cytokine profile and production

Multiple studies have analyzed the cytokine profile of offspring exposed to in utero MIA using various models, at different ages of the offspring, and in different sample types. Table 1 provides an overview of the reported alterations in the cytokine profile. The and online dataset is a searchable spreadsheet, which provides a more thorough summary of the cytokine profile, including the analyzed cytokines, the MIA model utilized, the age of the offspring, and the specific sample used. An acute effect of MIA was observed in the placenta after 48 h, with elevated levels of tumor necrosis factor alpha (Tnfα), interleukin (Il)-6, Il-12(p40) and a reduction in Il-10 [62].

Effect of MIA on the cytokine profile in the offsprings’ serum and plasma

Alterations in the cytokine profile in serum and plasma have been reported for different ages and models of the MIA exposed offspring. In the plasma of offspring exposed to poly (I: C), an elevation in Il-2, Il-5, and Il-6 was observed at postnatal day (PND)10, while no differences were observed for offspring exposed to LPS induced MIA [63]. Garay and colleagues [64] analyzed the serum cytokine profile of MIA exposed offspring from birth until adulthood. The cytokine profiles at birth, PND7, PND14, and PND30 were altered. However, alterations did not persist until adulthood. Moreover, the alterations found in the cytokine profile were not consistent during development [64]. In the serum of MIA exposed offspring, increases in Il-12(p40) and RANTES (regulated upon activation normal T cell expressed and secreted) and decreased levels of Il-3, granulocyte-macrophage colony-stimulated factor (GM-CSF), and macrophage inflammatory protein (Mip)-1α were reported at birth. A different profile was present at PND7, with an increase in Il-1β, Il-3, Il-6, Il-12(p40), granulocyte colony-stimulating factor (G-CSF), interferon (Ifn)γ, RANTES, and Tnfα, and a decrease was found for Il-1α, Il-2, and Il-12(p70). All the cytokine levels, except for in Tnfα and Mip-1β, were back to baseline levels at PND14. There was an elevation in Il-1β, Il-6, and Il-9 and a decrease in Il-3 reported on PND30, while no differences in cytokine levels were found in adulthood (PND60) [64]. Others analyzed the serum or plasma cytokine profile in both adolescent and adult offspring. An elevation in Il-1β [65, 66] and Il-6 [65] was observed in adolescents, and an elevation in Il-1β [65,66,67], and Il-10 [65] was observed in adult offspring exposed to MIA. In contrast, a decrease in Il-6 and Tnfα was also reported in adolescent offspring, with a decrease in Il-2 and Ifnγ in adult offspring exposed to MIA [68]. Furthermore, no alterations in plasma cytokine profiles have been reported in adolescent and adult offspring [67, 69].

In a Wistar rat model, no differences in the serum cytokine profile were reported in MIA exposed adult offspring [70]. Alterations in cytokine production were demonstrated in a non-human primate model [71]. Serum concentrations of innate inflammatory cytokines Il-1β, Il-6, Il-12(p40), and Tnfα were elevated in one year old MIA exposed offspring. Il-1β levels remained elevated in the serum of 4-year-old MIA exposed offspring. In addition, concentrations of Th2 cytokines Il-4 and Il-13 were increased in MIA offspring at the age of 4 years [71].

After postnatal immune induction, alterations in the serum cytokine profile were reported in offspring exposed to MIA. Ifng gene expression was upregulated in 3–4 weeks old offspring exposed to in utero MIA. Moreover, serum Il-6 and Il-17 cytokines were increased 24 h after postnatal poly (I: C) injection [72]. Following LPS-induced shock, a dose-dependent increase in serum Tnfα was reported in adult MIA exposed offspring [73]. Hsueh and colleagues [65] observed an increase in Il-1β, Il-6, and Il-10 in the serum of adult MIA offspring. After immune induction with LPS, various cytokines, chemokines, and cell adhesion molecules (CAM) were elevated in the serum of adult MIA exposed offspring when compared to control offspring. For the cytokines, an increase in Tnfα, Il-1β, Il-6, Il-10, Il-12p40, Il-17a, and Ifnγ was observed. An increase in the chemokines monocyte chemoattractant protein (Mcp)-1, monokine induced by interferon gamma (Mig), Mip-1α, Mip-1β, and RANTES was reported. Elevation in the cell adhesion molecules L-selectin, P-selectin, and intracellular adhesion molecule (Icam)-1 was observed [65]. After immune induction with zymosan, a significantly higher amount of Il-6, Tnfα, and Il-10 was present in the peritoneal fluid of the MIA exposed offspring [74, 75].

In summary, the observed alterations in the serum and plasma cytokine profiles vary considerably in MIA exposed offspring. The cytokine profile varies not only between the ages of the offspring but also between the studies. Moreover, multiple studies reported more non-affected cytokine concentrations than altered cytokine concentrations. The above-described studies have different timing of induction of MIA, with mid-gestation and late-gestation induction of MIA. A systematic review with meta-analysis compared the timing, age of offspring and the effect of MIA on cytokine concentrations. An increase in Il-6 was observed for MIA exposed offspring, with a bigger impact for mid gestation poly (I: C) MIA induction. Furthermore, differences in Il-1β, Il-10 and Tnfα were reported without associations with the offspring’s age and gestational induction period [76].

Effect of MIA on in vitro cytokine production

Differences in cytokine production have also been observed in vitro for several cell types obtained from the offspring of murine MIA models. In vitro cultures of neonatal splenocytes (PND7) showed an increase in Il-1β and Tnfα and a decrease in Il-10 production [62]. The same increase in Il-1β and Tnfα production and decreased Il-10 production were observed when the splenocytes were stimulated with LPS [62]. An increased production of cytokines was observed for CD4+ T cells originating from the spleen and mesenteric lymph nodes of adult offspring. Furthermore, in vitro stimulation of the CD4+ T cells resulted in elevated production of Il-6 and Il-17 [77]. CD4+ T cells of MIA exposed offspring showed elevated Th1/Th17 cytokine production from the spleen and Th17 cytokine production from the liver [73]. Bone marrow derived macrophages of MIA exposed adult offspring produced more Il-12(p40) and Mip-1α when LPS was added to the in vitro culture [78]. This increased Il-12(p40) and Mip-1α was also observed for polarized M1 macrophages stimulated with LPS [74]. Polarization toward M2 macrophages with LPS stimulation resulted in an increase in Il-1β and Mip-1α cytokine production [78].

Peripheral blood mononuclear cells (PBMC) in vitro culture from the non-human primate model showed elevated cytokine production for 1- and 4-year old MIA exposed offspring [71]. Elevated production of Il-6, Il-12(p40), Tnfα, G-CSF, GM-CSF, Mip-1α, and Mip-1β was found at baseline and after stimulation in PBMC culture of 1-year old MIA exposed offspring. At 4-years of age, an elevated production of Il-1β, G-CSF, and Mcp-1 was observed at baseline and after immune stimulation. There are similarities between plasma and in vitro PBMC cytokine production for the MIA exposed offspring at 1 year old. Both profiles demonstrate an increase in Il-2, Tnfα, Ifnγ, and G-CSF. However, the production of 11 cytokines was increased in the in vitro PBMC culture, while only an increase for 5 cytokines was found in the plasma [71]. The same applies to the plasma and in vitro PBMC cytokine production assessed at the age of 4 years, with an increase for Il-10, Cxcl8, and Mcp-1 in both profiles. An increased production of 6 cytokines was observed in the in vitro PBMC culture, while five cytokines were increased in the plasma [71].

Effect of MIA on the cytokine profile in the offspring’s brain

As previously stated, most studies using preclinical MIA models concentrate on the association between MIA and neurodevelopmental disorders. Numerous studies have analyzed the cytokine profile in the brains of the offspring at various ages and brain regions. (Tables 1 and online dataset). The cytokine patterns in the brain of the offspring were affected by the timing, severity, and interval between induction and analysis of MIA throughout gestation [79]. A meta-analysis of the offspring’s cytokine levels, however, did not support this [76].

The cytokine profile in the offspring’s brain was examined as early as three hours following MIA induction. In the fetal brain, three hours after mid-gestation (GD9) MIA induction, an increase in Il-6 and a decrease in Il-1β and Il-10 was observed. Six hours after MIA induction, an elevation in Il-1β and Il-6 was observed [79]. The fetal brain of offspring exposed to late gestational MIA (GD17) showed the opposite cytokine profile, with a decrease in Il-6 and an increase in ll-1β and Il-10 three hours after MIA exposure. The only change seen six hours after late gestational MIA was an elevation in Il-6 [79]. Alterations were observed in the fetal brain for pro-inflammatory cytokines, chemokines, and colony stimulating factors six and 24 h after MIA induction on GD16 [80]. 48 h after MIA induction on GD12, an increase in Il-12(p40) [62], Il-17α and Il-6 [81] was observed in the fetal brain. Interestingly, oral probiotic administration during pregnancy prevented the increase of Il-17α and Il-6 in the fetal brain [81]. Induction of MIA between GD15 and GD17 resulted in an elevation of Tnfα in the fetal brain on GD18, while no differences were observed at PND10 [63].

Besides the fetal and neonatal brains, the cytokine profiles of MIA exposed offspring have also been analyzed in the adolescent and adult brains. Multiple studies analyzed the cytokine profile in the offspring brain for different brain regions during development, revealing alterations in the brain cytokine profile for offspring exposed to MIA throughout development that were region-specific [64, 82]. Garay and colleagues [64] analyzed the cytokine profile in the frontal cortex, cingulate cortex, and hippocampus from birth until adulthood, besides the previously mentioned serum cytokine profile. In the frontal cortex, 18 different cytokines were altered during development. In the cingulate cortex, 17 different cytokines were altered throughout development. None of the cytokines were altered at all ages. In the hippocampus, 14 different cytokines were altered at birth or during development [60]. Overall, cytokine levels were elevated at birth, reduced during postnatal brain development, and increased in adulthood in the frontal and cingulate cortex of MIA exposed offspring. The cytokine alterations in the hippocampus had a mixed profile, with both increases and decreases between the ages. There were no similarities between the serum and region-specific cytokine profiles in MIA exposed offspring. The cytokine profiles from the serum and the region-specific brain varied [64]. The cytokine profile in the hippocampus of MIA exposed offspring was analyzed in multiple studies. In adult offspring, an increase in Il-1β was reported [67]. Nevertheless, no persistent systemic inflammation was observed in the hippocampus of adolescent and adult offspring exposed to in utero MIA [67]. In aged MIA exposed offspring, an increase in Il-1β and Il-6 was reported in the hippocampus [66]. Following postnatal immune induction, an increase in several cytokines, chemokines, and cell adhesion molecules was reported in the brains of adult MIA exposed offspring [65]. In contrast, no alterations in pro- and anti-inflammatory cytokines were reported in the hippocampus of adolescent, adult, and aged offspring exposed to GD17 induced MIA [69]. The cytokine profile in the cerebellum of MIA exposed offspring from birth until adolescence was also analyzed [82]. The cytokine profile in the cerebellum of MIA exposed offspring was mixed, with increases, decreases, and no differences in levels of different cytokines at different ages [82].

Furthermore, sex-specific and brain-region specific alterations were reported. In female adult MIA exposed offspring, an increase in Il-1β, Il-6 was observed in the amygdala and an increase in Tgf-β was observed in the hippocampus, while no alterations were found in the male MIA exposed offspring brain [83]. In both male and female offspring exposed to MIA, Il-10 was altered in the medial prefrontal cortex and hippocampus. However, in male offspring a decrease in Il-10 was observed, while an increase was found for female offspring [83].

In summary, alterations in the cytokine profile have been reported in the MIA exposed offspring’s brain. The cytokine profiles do not only vary between studies but are also region-specific and sex-specific. A thorough summary of the cytokine profile can be found in the and online dataset.

Effect of MIA on the immune related transcriptional profile in the offspring’s brain

Along with the differences in cytokine profiles, there were also differences reported for immune-related genes in the brains of MIA exposed offspring. Following MIA induction on GD12, differences in gene expression of Il1b, Il6, Tnfa, Il10, and Mcp1 were observed during brain development [84]. The differences in gene expression varied between the ages of the offspring [84]. Another study reported that MIA induced alterations in the gene expression of genes associated with inflammatory signaling, Il-2 stimulated pathways, selectin, developmental signaling, hormones, and synaptic structure were upregulated [65]. In a rat model, altered gene expression was observed in the hippocampus of adult MIA exposed offspring. For both LPS and poly I: C induced MIA, an increase in gene expression was observed for Il1b and Il18 in the hippocampus. Furthermore, an increase in gene expression was found for toll-like receptors (TLRs) and inflammasome pathway related genes [85].

Carlezon and colleagues [83] identified alterations in gene expression in the brains of MIA exposed offspring, in addition to previously mentioned alterations in protein cytokine profiles that were sex and brain region-specific. In female MIA exposed adult offspring, there was an increase in ll1b and Il6 gene expression observed in the medial frontal cortex, amygdala, and hippocampus. However, only an increase in Il-1β and Il-6 proteins was observed in the amygdala. An increase in Tgf-β1 was observed in the hippocampus of female offspring, which corresponds with the observed elevated gene expression [83]. In both male and female offspring, differences in anti-inflammatory factor Il10 gene expression were observed in the medial prefrontal cortex and hippocampus. Il10 gene expression was higher in females and lower in male MIA exposed offspring. This was consistent with the findings of altered Il-10 protein in both male and female offspring [83]. While there was no change in the IL-6 protein expression in male offspring, increased Il6 gene expression was observed in the medial prefrontal cortex and amygdala [83]. Male MIA exposed offspring had elevated Tnfa gene expression in the medial prefrontal cortex and thalamus. The Tnfa gene expression was elevated in the hippocampus of the female MIA exposed offspring [83].

In summary, alterations in the gene expression of cytokines have been reported in the MIA exposed offspring’s brain.