Elevated maternal cytokine levels at birth and risk for psychosis in adult offspring

Abstract

Background

Pregnancy and birth complications, particularly those associated with maternal inflammation and fetal hypoxia, are associated with increased risk for schizophrenia later in life. However, the molecular mechanisms underlying these associations are not fully delineated. This study sought to examine the effect of exposure to maternal inflammation on risk of developing psychosis in adulthood. Maternal serum levels of pro-inflammatory Th1 cytokines (IL-2, interferon gamma [IFN-γ], IL-12) and Th17 cytokines (IL-1b, IL-6, IL-8, tumor necrosis factor alpha [TNF-α], granulocyte macrophage colony stimulating factor [gm-csf]) and anti-inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10) were evaluated for association with later psychosis in the offspring.

Methods

Subjects were 43 adults with psychoses and 43 matched controls followed from gestation as part of the Philadelphia cohort of the National Collaborative Perinatal Project. Adult symptoms of psychosis were assessed via medical records review and confirmed with a validation study. Archived maternal serum samples collected at the time of birth were analyzed for cytokine levels using a multiplex bead assay.

Results

Individuals exposed to elevated maternal levels of anti-inflammatory Th2 cytokines (≥ 75th percentile) were significantly less likely to develop psychosis in adulthood.

Conclusions

These results may suggest that increased maternal levels of anti-inflammatory cytokines during the perinatal period could protect against the development of psychosis.

Introduction

Disruptions during prenatal and perinatal development, such as exposure to infection or hypoxia, are established risk factors for schizophrenia. As most pathogens are unable to cross the placental barrier, neural damage resulting from the maternal inflammatory response to infection is thought to be the mechanism that links prenatal infection with increased risk for schizophrenia (Brown and Derkits, 2010, Fineberg and Ellman, 2013). Similarly, hypoxia is thought to increase risk for schizophrenia via neural damage from excitotoxic and inflammatory processes (Leonardo and Pennypacker, 2009). Thus, inflammation has been proposed as a potential common mediator of perinatal risk factors for schizophrenia (Cannon, 2014, Miller et al., 2013); however, the precise molecular mechanisms that link perinatal inflammation with the development of schizophrenia remain unclear.

Cytokines are a prominent candidate for mediating the association between inflammation and schizophrenia. As cytokines are key regulators of both the immune response to pathogens (Block et al., 2007, Miller et al., 2013) and of prenatal neurodevelopment (Ratnayake et al., 2013), alterations in cytokine levels resulting from inflammation may disrupt normative neural development (Deverman and Patterson, 2009) and increase risk for developing schizophrenia (Miller et al., 2013, Monji et al., 2009). Cytokines are produced and secreted by both immune and non-immune cells, and are often broadly characterized as either promoting or inhibiting inflammation (Meyer, 2013). Rodent studies have established that perinatal exposure to pro-inflammatory cytokines can lead to neural changes that resemble those observed in schizophrenia, including altered morphology of cortical pyramidal cell dendrites (Weir et al., 2015) and elevated levels of activated microglia (Boksa, 2010, Tanaka et al., 2006). Human studies have demonstrated a greater risk for schizophrenia among offspring exposed to elevated levels of the pro-inflammatory cytokines interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α) in maternal serum in mid to late pregnancy (Brown et al., 2004, Buka et al., 2001, Ellman et al., 2010). There is emerging evidence in the rodent literature that high levels of anti-inflammatory cytokines can protect against inflammation-induced neural damage (Rodts-Palenik et al., 2004), which suggests that cytokine imbalance may play a critical role in the development of schizophrenia (Meyer et al., 2011, Miller et al., 2013). However, very little is known about the effect of perinatal exposure to anti-inflammatory cytokines on the risk of developing schizophrenia in humans.

One approach that may yield greater insight into the mechanisms by which cytokine exposure affects development is to group cytokines in a biologically plausible manner. As cytokines are released by a variety of immune cell types (e.g. macrophages, dendritic cells) (Zhou et al., 2010) and the effect of cytokines on inflammatory processes can vary by context (e.g. IL-10) (Meyer et al., 2008), identifying cytokines that typically signal together and have similar functions can be challenging. One potential approach is grouping cytokines by their association with CD4 + T helper cell (Th) signaling pathways. Th cells are commonly categorized into four main subtypes: Th1 and Th17, which tend to release cytokines that promote inflammation, and Th2 and T regulatory (Treg) cells, which generally release anti-inflammatory cytokines (O'Connor et al., 2014). Though some investigations of inflammation in schizophrenia have interpreted cytokines in the context of Th1 and Th2 activity (Monji et al., 2013, Potvin et al., 2008), there is a paucity of studies that incorporate the recently discovered Th17 and Treg categories or that examine a composite of multiple cytokines associated with specific Th subtypes.

The objective of this study was to examine the effect of exposure to maternal inflammation on the risk of developing psychosis in adulthood. To examine the role of cytokine exposure on risk for psychosis, maternal serum levels of pro-inflammatory Th1 cytokines (IL-2, IL-12, and interferon gamma [IFN-γ]) and Th17 cytokines (IL-1b, IL-6, IL-8, TNF-α, granulocyte macrophage colony stimulating factor [gm-csf]), and anti-inflammatory Th2 cytokines (IL-4, IL-5, and IL-13) and Treg cytokines (IL-10), were evaluated for association with later psychosis in the offspring.