Dysregulated placental expression of kynurenine pathway enzymes is associated with inflammation and depression in pregnancy.

BACKGROUND: Perinatal depression (including antenatal-, postnatal-, and depression that spans both timepoints) is a prevalent disorder with high morbidity that affects both mother and child. Even though the full biological blueprints of perinatal depression remain incomplete, multiple studies indicate that, at least for antenatal depression, the disorder has an inflammatory component likely linked to a dysregulation of the enzymatic kynurenine pathway. The production of neuroactive metabolites in this pathway, including quinolinic acid (QUIN), is upregulated in the placenta due to the multiple immunological roles of the metabolites during pregnancy. Since neuroactive metabolites produced by the pathway also may affect mood by directly affecting glutamate neurotransmission, we sought to investigate whether the placental expression of kynurenine pathway enzymes controlling QUIN production was associated with both peripheral inflammation and depressive symptoms during pregnancy. METHODS: 68 placentas obtained at birth were analyzed using qPCR to determine the expression of kynurenine pathway enzymes. Cytokines and metabolites were quantified in plasma using high-sensitivity electroluminescence and ultra-performance liquid chromatography, respectively. Maternal depressive symptoms were assessed using the Edinburgh Postnatal Depression Scale (EPDS) throughout pregnancy and the post-partum. Associations between these factors were assessed using robust linear regression with ranked enzymes. RESULTS: Low placental quinolinate phosphoribosyl transferase (QPRT), the enzyme responsible for degrading QUIN, was associated with higher IL-6 and higher QUIN/kynurenic acid ratios at the 3rd trimester. Moreover, women with severe depressive symptoms in the 3rd trimester had significantly lower placental expression of both QPRT and 2-amino-3-carboxymuconate-6-semialdehyde decarboxylase (ACMSD); impaired activity of these two enzymes leads to QUIN accumulation. CONCLUSION: Overall, our data support that a compromised placental environment, featuring low expression of critical kynurenine pathway enzymes is associated with increased levels of plasma cytokines and the dysregulated kynurenine metabolite pattern observed in depressed women during pregnancy.

The Mexican Cavefish Mount a Rapid and Sustained Regenerative Response Following Skeletal Muscle Injury.

Physical injury and tissue damage is prevalent throughout the animal kingdom, with the ability to quickly and efficiently regenerate providing a selective advantage. The skeletal muscle possesses a uniquely large regenerative capacity within most vertebrates, and has thus become an important model for investigating cellular processes underpinning tissue regeneration. Following damage, the skeletal muscle mounts a complex regenerative cascade centered around dedicated muscle stem cells termed satellite cells. In non-injured muscle, satellite cells remain in a quiescent state, expressing the canonical marker Pax7 (Chen et al. 2020). However, following injury, satellite cells exit quiescence, enter the cell cycle to initiate proliferation, asymmetrically divide, and in many cases terminally differentiate into myoblasts, ultimately fusing with surrounding myoblasts and pre-existing muscle fibers to resolve the regenerative process (Chen et al. 2020).

Cytokines and tryptophan metabolites can predict depressive symptoms in pregnancy.

Depression during and after pregnancy affects up to 20% of pregnant women, but the biological underpinnings remain incompletely understood. As pregnancy progresses, the immune system changes to facilitate fetal development, leading to distinct fluctuations in the production of pro-inflammatory factors and neuroactive tryptophan metabolites throughout the peripartum period. Therefore, it is possible that depression in pregnancy could constitute a specific type of inflammation-induced depression. Both inflammatory factors and kynurenine metabolites impact neuroinflammation and glutamatergic neurotransmission and can therefore affect mood and behavior. To determine whether cytokines and kynurenine metabolites can predict the development of depression in pregnancy, we analyzed blood samples and clinical symptoms in 114 women during each trimester and the postpartum. We analyzed plasma IL-1ß, IL-2, -6, -8, -10, TNF, kynurenine, tryptophan, serotonin, kynurenic- quinolinic- and picolinic acids and used mixed-effects models to assess the association between biomarkers and depression severity. IL-1ß and IL-6 levels associated positively with severity of depressive symptoms across pregnancy and the postpartum, and that the odds of experiencing significant depressive symptoms increased by >30% per median absolute deviation for both IL-1ß and IL-6 (both P = 0.01). A combination of cytokines and kynurenine metabolites in the 2nd trimester had a >99% probability of accurately predicting 3rd trimester depression, with an ROC AUC > 0.8. Altogether, our work shows that cytokines and tryptophan metabolites can predict depression during pregnancy and could be useful as clinical markers of risk. Moreover, inflammation and kynurenine pathway enzymes should be considered possible therapeutic targets in peripartum depression.

IL-10: A possible immunobiological component of positive mental health in refugees.

Objective: As the number of refugees continues to rise, there is growing concern about the impact from trauma exposures on their mental health. However, there is a limited understanding of possible biological mechanisms contributing to the substantial inter-individual differences in trauma-related outcomes, especially as it relates to positive mental health. Only sparse work has focused on the biology of positive mental health, including energy and sleep, in trauma-exposed persons. In this study, we analyzed cytokines in blood from newly arrived refugees with differential trauma exposures in relationship to self-reported energy, as a key marker of positive mental health. Methods: Within the first month of arrival in the USA, 64 refugees from Iraq and Syria were interviewed. Refugees completed the clinical DSM-IV PTSD-Checklist Civilian Version (PCL-C), the Beck Anxiety Inventory (BAI), and the Hospital Anxiety and Depression Scale (HADS). Ten psychiatrically healthy non-refugee persons were used as healthy controls to compare levels of cytokines. Blood samples were collected at the time of the interview and subsequently analyzed for IL-1ß, IL-6, IL-8, IL-10, and TNF-α concentrations. Results: Energy correlated positively with current concentration ability and sleep quality, and negatively with stress, PCL-C, BAI and HADS scores (Spearman correlations, all p<0.05). Refugees had lower levels of IL-10 compared to controls (p<0.05). IL-10 levels in refugees correlated with higher energy levels (p<0.01). Conclusions: Results suggest that self-reported energy is a key component of positive mental health in newly arrived traumatized refugees. Additionally, the anti-inflammatory cytokine IL-10 could be a marker of, or causally associated with positive mental health. A better understanding of the balance between pro- and anti-inflammatory states in highly traumatized individuals has the potential to create more targeted and effective treatments with implications for long-term health outcomes.

Associations between estrogen and progesterone, the kynurenine pathway, and inflammation in the post-partum.

BACKGROUND: Depression during and after pregnancy is common, affecting at least 15% of women. Features of depression in pregnancy range from mild symptoms of disrupted mood and interest to severe depression and suicidal behavior. Previous studies suggest hormone- and immune dysregulations might contribute to post-partum depression, but consistent evidence is lacking. METHODS: A total of 163 women were included in the study in the post-partum. Peri-partum depression (PPD) was diagnosed using SCID interviews and depressive symptoms were quantified using the Edinburgh Perinatal Depression Rating Scale (EPDS), retrospectively long-term, as well as acutely. Plasma estrogen, progesterone, pro- and anti-inflammatory cytokines and kynurenine metabolites were measured in the post-partum. RESULTS: Higher estrogen and progesterone in the post-partum were linked to more severe depressive symptoms over pregnancy. In the post-partum, estrogen was positively correlated with the pro-inflammatory cytokine IL-6 and negatively correlated with kynurenine and picolinic acid. Conversely, progesterone was negatively correlated with IL-1ß and several metabolites in the kynurenine pathway, including quinolinic acid. LIMITATIONS: Associative study design, did not attempt to assess causality. Did not adjust hormone levels for medication effects. CONCLUSIONS: Our study suggests that higher sex hormones in the post-partum are linked to depression severity over pregnancy. Estrogen was coupled with a pro-inflammatory profile and neurotoxic kynurenine metabolites, whereas progesterone was linked to an anti-inflammatory profile in the post-partum.

Inflammation and kynurenine pathway dysregulation in post-partum women with severe and suicidal depression.

Depression during pregnancy and the post-partum is common, with severe cases resulting in suicidal behavior. Despite the urgent and unmet medical need, the biological underpinnings of peri-partum depression remain unclear. It has been suggested that it is triggered by dynamic changes of the immune system during pregnancy and at delivery. Therefore, we investigated whether a pro-inflammatory status in plasma, together with changes in the kynurenine pathway activity, is associated with the development of severe depression and suicidal behavior in the post-partum. Our cross-sectional study targets a unique, understudied population in which the pronounced severity of symptoms required hospitalization. We analyzed plasma IL-1ß, IL-2, IL-6, IL-8, TNF-α, tryptophan, serotonin, kynurenine, nicotinamide, quinolinic- and kynurenic acids in post-partum women diagnosed with peripartum onset depression (PPD) and healthy controls (n = 165). We assessed depression severity using the Edinburgh Postnatal Depression Scale and suicidality using the Columbia-Suicide Severity Rating Scale. We found that increased plasma IL-6 and IL-8 and reductions of serotonin, IL-2 and quinolinic acid were associated with the severity of depressive symptoms and increased the risk for PPD. Moreover, women with lower serotonin levels were at an increased risk for suicidal behavior, even when adjusting for depression severity, psychosocial factors, age BMI, and medication. Our results indicate that severe depression in the post-partum involves dysregulation of the immune response and the kynurenine pathway, with a concomitant reduction in serotonin levels. We propose that inflammatory cytokines and the kynurenine pathway are potential treatment targets in PPD, opening up the possibility of novel therapeutic strategies targeting the peripartum.

Altered Tryptophan Catabolism in Placentas From Women With Pre-eclampsia.

BACKGROUND: The kynurenine pathway enzymes, breaking down tryptophan, are abundant in placental tissue. These metabolites are involved in immunoregulatory mechanisms, although the role of this pathway in pre-eclampsia (PE) has only begun to be characterized. Here, we determined tryptophan and metabolite levels together with the expression of kynurenine pathway enzymes and inflammatory factors in placental tissue from women with and without PE. METHODS: Thirty-six placentas (18 PE and 18 controls) were analyzed for expression of kynurenine pathway enzymes indoleamine-2,3-dioxygenase (IDO1 and 2), tryptophan-2,3-dioxygenase (TDO), kynurenine-3-mono-oxygenase (KMO) and quinolinate phosphoribosyltransferase (QPRT) as well as interleukin (IL)-1ß, IL-6, and serum amyloid A (SAA). Tryptophan and kynurenine content were measured using high-pressure liquid chromatography and quinolinic acid was measured using gas chromatography-mass spectrometry. CONCLUSIONS: Tryptophan content was reduced in placentas from women with PE. There was an increased kynurenine/tryptophan ratio in placentas from women with PE but no significant change in downstream metabolites. We confirmed a reduction in IDO1 expression and found a compensatory increase in TDO expression in placentas from women with PE. SAA was reduced in PE placentas compared with controls. Our data show that tryptophan content and the inflammatory mediator SAA are both compromised in placentas from women with PE. Further studies on the role of tryptophan catabolism and mediators of inflammation in sustaining healthy immunobiological pathways in the placenta are warranted.

An inflammatory profile linked to increased suicide risk.

BACKGROUND: Suicide risk assessments are often challenging for clinicians, and therefore, biological markers are warranted as guiding tools in these assessments. Suicidal patients display increased cytokine levels in peripheral blood, although the composite inflammatory profile in the subjects is still unknown. It is also not yet established whether certain inflammatory changes are specific to suicidal subjects. To address this, we measured 45 immunobiological factors in peripheral blood and identified the biological profiles associated with cross-diagnostic suicide risk and depression, respectively. METHODS: Sixty-six women with mood and anxiety disorders underwent computerized adaptive testing for mental health, assessing depression and suicide risk. Weighted correlation network analysis was used to uncover system level associations between suicide risk, depression, and the immunobiological factors in plasma. Secondary regression models were used to establish the sensitivity of the results to potential confounders, including age, body mass index (BMI), treatment and symptoms of depression and anxiety. RESULTS: The biological profile of patients assessed to be at increased suicide risk differed from that associated with depression. At the system level, a biological cluster containing increased levels of interleukin-6, lymphocytes, monocytes, white blood cell count and polymorphonuclear leukocyte count significantly impacted suicide risk, with the latter two inferring the strongest influence. The cytokine interleukin-8 was independently and negatively associated with increased suicide risk. The results remained after adjusting for confounders. LIMITATIONS: This study is cross-sectional and not designed to prove causality. DISCUSSION: A unique immunobiological profile was linked to increased suicide risk. The profile was different from that observed in patients with depressive symptoms, and indicates that granulocyte mediated biological mechanisms could be activated in patients at risk for suicide.

Defining the diversity of phenotypic respecification using multiple cell lines and reprogramming regimens.

To better understand the basis of variation in cellular reprogramming, we performed experiments with two primary objectives: first, to determine the degree of difference, if any, in reprogramming efficiency among cells lines of a similar type after accounting for technical variables, and second, to compare the efficiency of conversion of multiple similar cell lines to two separate reprogramming regimens-induced neurons and induced skeletal muscle. Using two reprogramming regimens, it could be determined whether converted cells are likely derived from a distinct subpopulation that is generally susceptible to reprogramming or are derived from cells with an independent capacity for respecification to a given phenotype. Our results indicated that when technical components of the reprogramming regimen were accounted for, reprogramming efficiency was reproducible within a given primary fibroblast line but varied dramatically between lines. The disparity in reprogramming efficiency between lines was of sufficient magnitude to account for some discrepancies in published results. We also found that the efficiency of conversion to one phenotype was not predictive of reprogramming to the alternate phenotype, suggesting that the capacity for reprogramming does not arise from a specific subpopulation with a generally "weak grip" on cellular identity. Our findings suggest that parallel testing of multiple cell lines from several sources may be needed to accurately assess the efficiency of direct reprogramming procedures, and that testing a larger number of fibroblast lines--even lines with similar origins--is likely the most direct means of improving reprogramming efficiency.