Lower inflammatory markers in women with antenatal depression brings the M1/M2 balance into focus from a new direction
Introduction
Symptoms of depression are common in pregnancy, and 4–7% of pregnant women fulfill the criteria for major depressive disorder (Andersson et al., 2003, Gorman et al., 2004, Melville et al., 2010, Patkar et al., 2004). Antenatal depression and use of serotonin reuptake inhibitors (SSRI) in pregnancy have both been associated with an increased risk of poor pregnancy outcomes, such as preterm birth and impaired fetal growth. While the underlying biological mechanisms for these complications are poorly understood (Olivier et al., 2013), it has been hypothesized that inflammation may be a common physiological pathway. Many obstetric complications, including preterm birth and preeclampsia, have been associated with increased inflammatory response, and the same is true for major depression, or treatment thereof (Osborne and Monk, 2013).
During normal pregnancy the immune system undergoes numerous changes to protect the woman from pathogens while at the same time avoiding alienation of the semi-allogeneic fetus (La Rocca et al., 2014). Pregnancy-induced changes in progesterone, estradiol, leukaemic inhibitory factor, and prostaglandins are likely to be partially responsible for the switch from high levels of Type 1 T helper (Th1) cells in early pregnancy to high levels of Type 2 T helper (Th2) cells in late pregnancy (Mjosberg et al., 2010, Sykes et al., 2012). The picture may, however, be slightly more complex as other studies indicate that both Th1 and Th2 responses are limited during pregnancy, and the innate immune system may play a greater role than previously thought (Kraus et al., 2012, Luppi et al., 2002). Recently, the role of peripheral and central macrophages (microglia) in initiating and regulating pro-inflammatory and anti-inflammatory states has come into focus, with repercussion for pregnancy as well (Jones and Thomsen, 2013, Nagamatsu and Schust, 2010a, Nagamatsu and Schust, 2010b). Macrophages are plastic cells, which can switch from the classic pro-inflammatory M1 state and associated elevated levels of tumor necrosis factor alpha (TNF-α), interleukin (IL)-6 and IL-1β to an alternative state; the M2 macrophages, induced by IL-4 and IL-13, and producing IL-10, IL-4, and transforming growth factor beta (TGF-β) (Martinez and Gordon, 2014, Wang et al., 2014). M2 macrophages are involved in wound healing and tissue remodeling tasks, with additional contributions to the metabolic performance and the endocrine signaling of the tissues (Martinez and Gordon, 2014). Early pregnancy is characterized by an increase in M1 macrophages, however, once the placenta is developed, a shift to a predominantly pro-M2 milieu occurs, preventing fetal rejection until parturition (Brown et al., 2014). Reduced levels of pro-inflammatory cytokines, IL-2 and INF-γ are found during the second trimester (Shimaoka et al., 2000), and the pro-M2 milieu continues into the third trimester (Kraus et al., 2010). Finally, immediately prior to delivery, a last inflammatory phase is noted, characterized by high levels of pro-inflammatory cytokines both in cervical tissue (Dubicke et al., 2010, Malmstrom et al., 2007, Sennstrom et al., 2000), and in circulating blood (Fransson et al., 2012, Luppi et al., 2002). The pregnancy-induced cortisol increase also contributes to the anti-inflammatory response during the second and third trimesters. For protection of the fetus, most of the maternal cortisol is converted to inactive cortisone by the enzyme 11-beta hydroxysteroid dehydrogenase (11b-HSD) (Murphy et al., 1974), and the maternal serum cortisone to cortisol ratio is likely to reflect maternal and placental 11β-HSD2 activity. The inflammatory status of macrophages is controlled by a number of nuclear receptors, including the glucocorticoid receptor, and it was recently shown that 11β-HSD1 enzyme activity is higher in M2 macrophages than in M1 macrophages, (Chinetti-Gbaguidi et al., 2012).
A bidirectional communication between the immune system and the central nervous system is essential for normal brain functions, such as initiating and regulating stress responses, emotions and behavior (Miller and Raison, 2015). Sickness behavior induced by pro-inflammatory cytokines resembles major depressive disorder, and interferon alpha (INF-α) treatment induces major depressive disorder in 25% of patients, suggesting a causal mechanism (Dantzer, 2001, Udina et al., 2012). In non-pregnant subjects, peripheral pro-inflammatory markers such as IL-6, IL-1β, IFN-α, TNF-α, and the chemokine monocyte chemoattractant protein 1 (MCP1)/chemokine (CC motif) ligand 2 (CCL2) are increased in the blood and cerebrospinal fluid of a subgroup of patients with mood disorders versus healthy controls, both when assessed at baseline and after exposure to stressors (Dowlati et al., 2010, Jones and Thomsen, 2013, Miller et al., 2009). Similarly, the current knowledge indicates that shifts toward M1 macrophages in the M1/M2 balance may be related to depression development in the non-pregnant population (Bhattacharya et al., 2016, Jones and Thomsen, 2013, Miller and Raison, 2015).
While the inflammatory response has been extensively studied in obstetric complications such as preterm birth and preeclampsia, studies on the role of peripheral inflammatory markers in antenatal depression are thus far few. In addition, the extent of evaluated markers has, with one exception, been limited to IL-6, IL-10, IL-1β, and TNF-α (Blackmore et al., 2011, Cassidy-Bushrow et al., 2012, Christian et al., 2009, Shelton et al., 2015). Thus far, findings can at best be described as inconsistent with unchanged, increased or decreased levels of cytokines and other inflammatory markers in women suffering from antenatal depression (Blackmore et al., 2011, Cassidy-Bushrow et al., 2012, Christian et al., 2009, Shelton et al., 2015). Different immunological stages during pregnancy may potentially explain these inconsistencies.
Thus, given the limited information on how the inflammatory response in pregnancy influences the risk of antenatal depression, the aim of the present study was to assess peripheral inflammatory markers during the third trimester in healthy women, women with antenatal depression and in women using SSRI during pregnancy. A secondary aim was to evaluate the usefulness of these markers for the purpose of diagnosing antenatal depression.
Section snippets
Participants
This sub-study to the cohort study ‘Biology, Affect, Stress, Imaging, and Cognition in pregnancy and the puerperium’ (BASIC) consisted of 160 healthy pregnant controls, 59 women with antenatal depression and 39 women on treatment with SSRIs. BASIC is an ongoing longitudinal study that aims to investigate mood disorders in pregnancy and postpartum. All women over the age of 18 years in Uppsala County who attend their routine ultrasound in gestational week 16–18 are invited to participate in the
Participants
Demographic data for the study group is displayed in Table 1. The three groups; healthy controls, women with antenatal depression, and women using SSRI did not differ in terms of marital status, parity, smoking and alcohol use, or self-reported sleep disturbances. Similarly, prevalence of inflammatory diseases and obstetric complications, such as preeclampsia or hypertension, were similar between groups. However, women with antenatal depression were significantly younger, and had completed
Discussion
The major finding of the present study was that women with antenatal depression and women on SSRI treatment had significantly lower levels of peripheral inflammatory markers than healthy pregnant controls, for as many as 23 markers. These findings are seemingly at odds with the literature in non-pregnant samples, where depression has been associated with increased levels of proinflammatory cytokines (Dantzer, 2001, Dowlati et al., 2010, Jones and Thomsen, 2013, Miller et al., 2009, Udina et
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2021, Brain, Behavior, and Immunity - HealthCitation Excerpt :Studies on pregnant women point at diverse and complex links between the immune response adaptation and perinatal mood. Some studies report on increase in pro-inflammatory activity in early antenatal depression (Christian, Franco, Glaser, et al., 2009; Haeri, Baker and Ruano, 2013), we have shown that antenatal depressive symptoms associate with lower regulatory or anti-inflammatory markers in late pregnancy (Edvinsson et al., 2017). In another study, Osborne et al. (2019) found an increase in pro-inflammatory cytokines during the third trimester in women with higher levels of depressive symptoms.
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