Inflammation In Adulthood Research Articles

Early origins of socioeconomic inequalities in chronic inflammation: Evaluating the contributions of low birth weight and short breastfeeding.

The United States is characterized by persistent and widening social inequities in a wide range of adult health outcomes. A life course approach challenges us to consider if, and how, these inequities trace back to early life conditions, and chronic inflammation represents a potentially important mechanism through which early environments may have lasting effects on health in adulthood. Low birth weight (LBW) and shorter durations of breastfeeding both predict increased inflammation in adulthood, which is associated with increased risk for cardiovascular disease, metabolic syndrome, and all-cause mortality. Using data from a large representative sample of young adults in the US (National Longitudinal Study of Adolescent to Adult Health (Add Health)), we document the socioeconomic status (SES) gradient in chronic inflammation, as indicated by concentrations of C-reactive protein (CRP). Using a nested set of structural equation models and marginal standardization techniques, we investigate the extent to which this gradient is explained by patterns of LBW and breastfeeding in infancy. Findings reveal a particularly important role for breastfeeding duration: Based on model predictive margins, increasing breastfeeding duration to three or more months corresponds to a flattening of the SES gradient by 80%, and 83% when LBW is eliminated. This study expands current understandings of the consequential role of developmental environments for population health and for addressing health inequities in future generations.

Early adult to midlife trajectory of inflammation and midlife cognition

AbstractBackgroundLate‐life inflammation, often measured by peripheral biomarkers, has been linked to risk of developing dementia and preclinical cognitive decline. Little is known about early adulthood inflammation and if this could influence cognition earlier in life. Furthermore, few studies have investigated repeated measures of inflammation.MethodWe studied 1920 adults (mean age 33.3 ±3.5, 53% female, 62% white) who were enrolled in the Coronary Artery Risk Development in Young Adults study. We used latent class analysis to identify inflammation trajectories using repeated C‐reactive protein (CRP) measurements (≥3 CRP assessments) over almost two decades. At midlife (mean age 55.4 ±3.5), we assessed cognition using the Digit Symbol Substitution Test (DSST), Stroop Test, Rey Auditory Verbal Learning Test, Montreal Cognitive Assessment, and fluency tests. Logistic regression was used to evaluate the association between inflammation trajectories and poor cognitive performance, defined as a score ≥1 standard deviation below the cohort mean for each test.ResultThree early to mid‐adult inflammation trajectories were identified: consistently low (34% [n=676]), moderate/increasing (15.0% [n=150]), and consistently high (51% [n=1094]). Those participants in the moderate/increasing or high trajectories had about a two‐fold greater risk (adjusting for age, race, sex, and education) of poor cognitive performance on processing speed and executive function tasks compared to those in the consistently low trajectory. Further adjustment for physical activity, smoking, alcohol, hypertension and diabetes led to similar results (DSST: moderate/increasing OR=2.11 95%CI 1.22‐3.65, high OR=1.52 95%CI 1.07‐2.15; Stroop: high OR=1.68 95%CI 1.16‐2.44). There were no differences by trajectory in odds of poor cognitive performance on memory or global cognition domains.ConclusionHigh or moderate/increasing early to mid‐adult inflammation trajectory was associated with an almost 2‐fold higher odds of worse executive function and processing speed in midlife. These findings suggest that inflammation is an important association for cognitive aging and may begin much earlier in life than previously known.

Annual Research Review: Social relationships and the immune system during development.

A child's social relationships serve critical functions during development. The interface between a child's social world and their immune system, particularly innate immunity, which helped children survive in the face of infections, nutritional scarcity, and violence throughout human history, is the focus of this Annual Research Review. This article reviews the state of research on social relationships and innate immune inflammation during childhood. Warmth and rejection in childhood social relationships, as well as physical trauma and unpredictable social environments, were not consistently related to circulating inflammatory markers such as interleukin-6 and C-reactive protein during childhood. Instead, links between social environments and inflammation were observed in studies that focus on children with greater background risk factors, such as low family socioeconomic status, family history of mood disorders, or presence of chronic interpersonal stressors combined with acute episodic stressors. In addition, studies on worse childhood social environments and greater inflammation in adulthood were more consistent. Warmth and rejection in the social environment may be related to sensitivity of immune cells to the anti-inflammatory actions of glucocorticoids, though this is primarily observed in adolescent women at risk for depression. Additional mechanistic evidence suggests that greater warmth and less rejection are related to processes that regulate inflammation, including greater expression of the glucocorticoid receptor gene and lower expression of genes that are responsive to the pro-inflammatory transcription factor NF-kappa B. The article concludes by discussing implications of the interface between a child's social relationships and inflammation for mental health and other recent (on evolutionary timescales) health threats, as well as recommendations for future research, and recommendations for researchers interested in integrating inflammatory measures in developmental research.

Maternal childhood adversity and inflammation during pregnancy: Interactions with diet quality and depressive symptoms

Inflammatory processes are a candidate mechanism by which early adversity may be biologically embedded and subsequently lead to poorer health outcomes; in pregnancy, this has been posited as a pathway for intergenerational transmission of adversity. Studies in non-pregnant adults suggest that factors such as mood, diet, BMI, and social support may moderate associations between childhood trauma history and inflammation in adulthood, though few studies have examined these associations among pregnant women. In a sample of healthy pregnant women (N = 187), we analyzed associations between maternal childhood adversity, including maltreatment and non-optimal caregiving experiences, with circulating Interleukin-6 (IL-6) levels during trimesters 2 (T2) and 3 (T3) of pregnancy. We also assessed whether these associations were moderated by psychosocial and lifestyle factors including depressive symptoms, social support, physical activity, and diet quality. History of childhood maltreatment was not associated with IL-6 in either T2 or T3 of pregnancy, either independently or in interaction with depressive symptom severity. However, in there was a significant positive association between childhood maltreatment and IL-6 in Trimester 2 in the context of poorer diet quality (p = 0.01), even after adjusting for BMI. Additionally, the quality of caregiving women received in childhood was associated with levels of IL-6 in Trimester 3, but only via interaction with concurrent depressive symptoms (p = 0.02). These findings provide evidence that for those with a history of childhood adversity, levels of inflammatory cytokines in pregnancy may be more sensitive to depressive symptoms and diet quality.

Maltreatment exposure across childhood and low-grade inflammation: Considerations of exposure type, timing, and sex differences.

Links between child maltreatment and low-grade inflammation in adulthood are well documented, but these studies often rely on adults to report retrospectively on experiences of childhood abuse. Furthermore, these findings raise questions about whether exposure to childhood maltreatment needs time to "incubate," only giving rise to nonresolving inflammation in adulthood, or whether heightened inflammation may be observable in childhood, closer in time to the maltreatment exposure. The present study examined this question in a sample of 155 low-income children (ages 8-12), half of whom had been exposed to maltreatment. Trained coders evaluated case reports to classify maltreatment based on timing and exposure type. Blood samples from children assessed C-reactive protein and cytokines, which were used to form a composite of low-grade inflammation. Analyses revealed a marginally significant Maltreatment Exposure×Sex interaction, which suggested that maltreatment exposure was associated with higher inflammation for girls but not boys. Additionally, analyses focused on the accumulation of maltreatment experiences (through multiple forms of maltreatment or across multiple time points) revealed that girls with greater diversity in their maltreatment experiences and those who experienced maltreatment at multiple time points were at greatest risk. Finally, examination of timing of first onset of maltreatment suggested that girls whose exposures occurred before the age of 5 had the highest low-grade inflammation. These findings add new evidence linking maltreatment to inflammation in childhood, which could increase the risk for mental and physical health problems across the lifespan.

Trust as a mediator in the relationship between childhood sexual abuse and IL-6 level in adulthood.

Childhood sexual abuse (CSA) has been shown to predict the coupling of depression and inflammation in adulthood. Trust within intimate relationships, a core element in marital relations, has been shown to predict positive physical and mental health outcomes, but the mediating role of trust in partners in the association between CSA and inflammation in adulthood requires further study. The present study aimed to examine the impact of CSA on inflammatory biomarkers (IL-6 and IL-1β) in adults with depression and the mediating role of trust. A cross-sectional survey data set of adults presenting with mood and sleep disturbance was used in the analysis. CSA demonstrated a significant negative correlation with IL-6 level (r = -0.28, p<0. 01) in adults with clinically significant depression, while trust showed a significant positive correlation with IL-6 level (r = 0.36, p < .01). Sobel test and bootstrapping revealed a significant mediating role for trust between CSA and IL-6 level. CSA and trust in partners were revealed to have significant associations with IL-6 level in adulthood. Counterintuitively, the directions of association were not those expected. Trust played a mediating role between CSA and adulthood levels of IL-6. Plausible explanations for these counterintuitive findings are discussed.

Presentation and Treatment of Deep Orbital Dermoid Cysts

Periocular dermoids usually are preseptal (exophytic)1 and present in infancy, whereas the much rarer deep orbital (endophytic)1 ones often present with inflammation in adulthood.1–5 Using review of records, imaging, and pathologic analysis, we described the characteristics, management, and outcomes for 82 patients with deep orbital dermoid cysts (DODCs) treated at Moorfields Eye Hospital between 1992 and 2017. The study was approved by the institutional review board at Moorfields Eye Hospital (identifier, MEH no.

Neonatal Injury Increases Gut Permeability by Epigenetically Suppressing E-Cadherin in Adulthood.

Altered intestinal epithelial integrity is an important susceptibility trait in inflammatory bowel disease (IBD), and early life stressors are reported to contribute to this disease susceptibility in adulthood. To identify disease mechanisms associated with early-life trauma that exacerbate IBD in adulthood, we used a "double-hit" neonatal inflammation (NI) and adult inflammation (AI) model that exhibits more severe mucosal injury in the colon later in life. In this study, we explore the underlying mechanisms of this aggravated injury. In rats exposed to both NI and AI, we found sustained increases in colonic permeability accompanied by significantly attenuated expression of the epithelial junction protein E-cadherin. Quantitative RT-PCR revealed a decreased Cdh1 (gene of E-cadherin) mRNA expression in NI + AI rats compared with NI or AI rats. Next, we performed microRNA microarrays to identify potential regulators of E-cadherin in NI + AI rats. We confirmed the overexpression of miR-155, a predicted regulator of E-cadherin, and selected it for further analysis based on reported significance in human IBD. Using ingenuity pathway analysis software, the targets and related canonical pathway of miR-155 were analyzed. Mechanistic studies identified histone hyperacetylation at the Mir155 promoter in NI + AI rats, concomitant with elevated RNA polymerase II binding. In vitro, E-cadherin knockdown markedly increased epithelial cell permeability, as did overexpression of miR-155 mimics, which significantly suppressed E-cadherin protein. In vivo, NI + AI colonic permeability was significantly reversed with administration of miR-155 inhibitor rectally. Our collective findings indicate that early-life inflammatory stressors trigger a significant and sustained epithelial injury by suppressing E-cadherin through epigenetic mechanisms.

Severe but not moderate hyperoxia of newborn mice causes an emphysematous lung phenotype in adulthood without persisting oxidative stress and inflammation

BackgroundPreterm newborns typically require supplemental oxygen but hyperoxic conditions also damage the premature lung. Oxygen-induced lung damages are mainly studied in newborn mouse models using oxygen concentrations above 75% and looking at short-term effects. Therefore, we aimed at the investigation of long-term effects and their dependency on different oxygen concentrations.MethodsNewborn mice were exposed to moderate vs. severe hyperoxic air conditions (50 vs. 75% O2) for 14 days followed by a longer period of normoxic conditions. Lung-related parameters were collected at an age of 60 or 120 days.ResultsSevere hyperoxia caused lower alveolar density, enlargement of parenchymal air spaces and fragmented elastic fibers as well as higher lung compliance with peak airflow limitations and higher sensitivity to ventilation-mediated damages in later life. However, these long-term lung structural and functional changes did not restrict the voluntary physical activity. Also, they were not accompanied by ongoing inflammatory processes, increased formation of reactive oxygen species (ROS) or altered expressions of antioxidant enzymes (superoxide dismutases, catalase) and lung elasticity-relevant proteins (elastin, pro-surfactant proteins) in adulthood. In contrast to severe hyperoxia, moderate hyperoxia was less lung damaging but also not free of long-term effects (higher lung compliance without peak airflow limitations, increased ROS formation).ConclusionsSevere but not moderate neonatal hyperoxia causes emphysematous lungs without persisting oxidative stress and inflammation in adulthood. As the existing fragmentation of the elastic fibers seems to play a pivotal role, it indicates the usefulness of elastin-protecting compounds in the reduction of long-term oxygen-related lung damages.

Early life socioeconomic position and adult systemic inflammation: the role of gene regulation

Abstract Background Adverse socioeconomic conditions in childhood affect systemic low-grade inflammation in adulthood. Studies in animals and humans suggest that socioeconomic conditions get under the skin from early life thus contributing to shape pro-inflammatory phenotypes. Although the existence of socioeconomic differences in gene regulation of the immune function have been described previously, no study has so far assessed the extent to which these differences actually explain socioeconomic variations in inflammatory markers. Methods First, we ran 2-sample Mendelian Randomization (MR) methods to identify putative genes whose expression drives C-reactive protein (CRP) levels in blood. We used two databases with summary statistics of associations between single nucleotide polymorphisms and gene expression (eQTLGen, N = 31,486 individuals) and CRP (CHARGE, N = 148,164 individuals) in blood. We tested 10,701 genes and retained those with FDR&amp;lt;0.05. Second, we used individual-participant data from a Swiss population-based study (SKIPOGH, N = 723) to estimate the proportion of the effect of paternal occupational position (SEP) on low-grade inflammation in adulthood (CRP&amp;gt;3mg/L) mediated by the selected genes. We estimated odds ratios and mediated proportions through counterfactual-based mediation models. Results We identified 426 genes driving CRP levels (robust to unmeasured confounding thanks to MR). They jointly mediated the effect of low father’s occupation on inflammation in adulthood for a proportion up to about 70% [95% confidence intervals (CI) 11-90%] and with an odds ratio of 1.53 [95% CI 1.05-2.15] compared to individuals with high paternal SEP. Analysis of the effects of life-course SEP trajectories (upward, downward and stable low from paternal to adult SEP) on gene regulation revealed trajectory dependent effects. Conclusions We suggest that adverse childhood SEP affects systemic inflammation in adulthood through a long-lasting effect on gene regulation.

Social patterning of inflammation over the lifecourse and its relationship with mortality

Abstract Background This study explores (i) the relationship between socioeconomic position (SEP) across the life course and circulating C-reactive protein (CRP), a marker of systemic inflammation, in 6 European cohort studies (in up to N = 23 008) participating in the Lifepath project and (ii) interrogate the hypothesis of a cumulative biological risk (allostatic load, AL) reflecting 4 physiological systems, including inflammation, potentially predicting future risk of death in one of the cohort. Methods First, we estimated the association between measures of three time point SEP and adulthood CRP, adjusting for health behaviours and body mass index (BMI). To mimic life course experiences, we sequentially adjusted for the chronologically ordered measures of SEP. Next we used mortality data from the 1958 British birth cohort to operationalise AL from 14 biomarkers collected at age 44. Multivariate Cox proportional hazards regression was used to estimate hazard ratios for the association between AL, biological sub-scores and individual biomarkers with mortality. Results Educational attainment was most strongly related to inflammation where low educational attainment was associated with higher log-transformed levels of CRP (β = 0.30, (0.22-0.38)). Higher AL at 44 years old was a significant predictor of mortality 11 years later (HR = 3.56 (2.3 to 5.53)). Among the four physiological systems, only the immune-inflammatory and cardiovascular sub-scores were significantly related to mortality. Conclusions Socioeconomic circumstances across the life course are associated with higher levels of inflammation in adulthood which in turn predict subsequent risk of death. But our findings also suggest that the cumulative AL measure consisting of all the biomarkers was a better measure for predicting death adding evidence on the biological embodiment in response to chronic stress, suggesting that social-to-biological processes are at play, beyond the impact of health behaviours and BMI.

Chronic psychological stress during adolescence induces sex-dependent adulthood inflammation, increased adiposity, and abnormal behaviors that are ameliorated by selective inhibition of soluble tumor necrosis factor with XPro1595

Physical and psychosocial maltreatment experienced before the age of 18, termed early life adversity (ELA), affects an estimated 39% of the world’s population, and has long-term detrimental health and psychological outcomes. While adult phenotypes vary following ELA, inflammation and altered stress responsivity are pervasive. Cytokines, most notably tumor necrosis factor (TNF), are elevated in adults with a history of ELA. While soluble TNF (solTNF) drives chronic inflammatory disease, transmembrane TNF facilitates innate immunity. Here, we test whether solTNF mediates the behavioral and molecular outcomes of adolescent psychological stress by administering a brain permeable, selective inhibitor of solTNF, XPro1595. Male and female C57BL/6 mice were exposed to an aggressive rat through a perforated translucent ball (‘predatory stress’) or transported to an empty room for 30 min for 30 days starting on postnatal day 34. Mice were given XPro1595 or vehicle treatment across the last 15 days. Social interaction, sucrose preference, and plasma inflammation were measured at 2 and 4 weeks, and open field behavior, adiposity, and neuroinflammation were measured at 4 weeks. Chronic adolescent stress resulted in increased peripheral inflammation and dysregulated neuroinflammation in adulthood in a sex-specific manner. Abnormal social and open field behavior, fat pad weight, and fecal boli deposition were noted after 30 days; solTNF antagonism ameliorated the effects of stress. Together, these data support our hypothesis, and suggest that targeting solTNF with XPro1595 may improve quality of life for individuals with a history of adolescent stress.

Childhood Adversity and Current Stress are related to Pro- and Anti-inflammatory Cytokines in Major Depression

BackgroundStress during early childhood, for example as a result of maltreatment, can predict inflammation in adulthood. The association of depression with inflammation and current and long-term stress resulting from childhood maltreatment and threatening experiences in the past year has not yet been studied. Therefore, we assessed these variables in a group of patients with major depressive disorder (MDD) and measured levels of the pro-inflammatory cytokine IL-6 and the anti-inflammatory cytokine IL-10. High levels of IL-6 are associated with depression and of IL-10 with stress. MethodsWe included 44 patients who fulfilled DSM-IV diagnostic criteria for MDD and 44 age- and gender-matched healthy controls. We used Cohen's Perceived Stress Scale (PSS), the list of life-threatening experiences questionnaire (LTE-Q) and the childhood trauma questionnaire (CTQ) to assess the level of stress and analyzed IL-6 and IL-10 cytokines in venous blood plasma. ResultsThe patient group showed significantly higher scores on the maltreatment scale LTE-Q (2.7 vs. 1.1; P = 0.001, and the stress scales CTQ (emotional abuse; P = 0.048 and physical neglect; P = 0.002) and PSS (35.2 vs 15.5; P < 0.001) as well as significantly higher levels of IL-6 (1.5pg/ml vs. 0.9pg/ml; P = 0.012). They also had significantly higher levels of IL-10 (1.1pg/ml vs. 0.7pg/ml; P < 0.001). Higher actual stress levels were associated with childhood maltreatment and higher IL-6 (tau = 0.004) and IL-10 (tau = 0.027) levels. LimitationsThe results need to be replicated in a larger sample, and the study did not evaluate causal relationships. Although the assessment of childhood trauma was retrospective, the CTQ is a well-established assessment instrument. ConclusionsThe patients with MDD in this study showed an immune activation in response to stress. This study highlights the association of childhood trauma and current and long-term stress with an increased immune activation in MDD.

Early-life vancomycin treatment promotes airway inflammation and impairs microbiome homeostasis.

Several studies have reported that gut and lung microbiomes are involved in the process of asthma pathogenesis. However, it remains unclear how perinatal or early-life antibiotic intervention affect adult allergic airway inflammation. We assigned C57BL/6 mice randomly to four experimental groups: normal saline control (NS), ovalbumin (OVA), vancomycin pretreated NS (VAN-NS), and vancomycin pretreated OVA (VAN-OVA). The vancomycin groups were orally given the drug from gestational day 14 to 6 week. An OVA-induced asthma model was then established at 6 weeks of age, and airway inflammation was evaluated. In addition, total DNA was extracted from the feces and lung tissue and used for 16S rDNA gene sequencing, to detect the composition of the microbiome. In the VAN-OVA group, airway inflammation and Th2-related cytokines were found to be significantly increased versus the control groups. Gene sequencing showed that vancomycin treatment attenuated the richness and evenness, and altered the composition of the microbiome in the gut and lung. Micrococcaceae and Clostridiaceae-1 were potentially correlated to the severity of allergic airway inflammation. Our study suggests that perinatal and early-life vancomycin intervention aggravates allergic inflammation in adulthood, which might be correlated with imbalanced gut and lung microbiome homeostasis.

Novel Genetic Locus of Visceral Fat and Systemic Inflammation.

Visceral fat (VF), more than fat elsewhere in the body [mostly subcutaneous fat (SF)], promotes systemic inflammation and related disease. The mechanisms of preferentially visceral accumulation of body fat are largely unknown. To identify genetic loci and mechanistic pathways of preferential accumulation of VF and associated low-grade systemic inflammation. Genome-wide association study (GWAS). Population-based cohort of 1586 adolescents (aged 12 to 19 years) and adults (aged 36 to 65 years). Abdominal VF and SF were measured with MRI, total body fat (TBF) was assessed with bioimpedance, and low-grade systemic inflammation was examined by serum C-reactive protein (CRP) measurement. This GWAS of preferential accumulation of VF identified a significant locus on chromosome 6 at rs803522 (P = 1.1 × 10-9 or 4.3 × 10-10 for VF adjusted for SF or TBF, respectively). The major allele was associated with more VF; the association was similar in adolescents and adults. The allele was also associated with higher CRP level, but this association was stronger in adults than adolescents (P for interaction = 4.5 × 10-3). In adults, VF was a significant mediator (P = 1.9× 10-4) in the association between the locus and CRP, explaining 30% of the mediation. The locus was near ATG5, encoding an autophagy molecule reported to modulate adipocyte size and macrophage polarization. A genetic locus near ATG5 regulates preferential accumulation of VF (vs SF) in youth and adulthood and contributes to the development of systemic inflammation in adulthood.

Maternal infections during pregnancy and offspring midlife inflammation

BackgroundMicrobial exposures early in life have been found to be associated with lower levels of inflammation in adulthood; however, the role of prenatal exposure to infection on offspring inflammatory profiles is unexplored. The aim was to study if maternal infections during pregnancy are associated with inflammation among offspring in later life and to determine if there are sensitive periods of exposure.MethodsThe study was comprised of 1719 participants in the Copenhagen Aging and Midlife Biobank (CAMB) who were also members of the Copenhagen Perinatal Cohort (CPC). When the CPC was established, information on maternal infections during pregnancy was prospectively collected by a trained medical doctor. The inflammatory measures collected in late midlife included, C-reactive protein (CRP), Interleukin-6 (IL-6), TNF-alpha (TNF-α) and Interleukin-10 (IL-10). Multivariable ordinary least squared regression models were implemented to explore associations between maternal infection and inflammatory measures in offspring, controlling for maternal smoking, pre-pregnancy body mass index, age, marital status and parity.ResultsMaternal infection was associated with a 7% lower CRP level (95% CI, − 17,5%) among offspring compared with offspring born to women without an infection and similarly an 8% lower level of IL-6 (95% CI -15,1%), and a 9% lower level of IL-10 (95% CI, − 23,20%). However, differences did not reach significance. The effects of infection during the first trimester did not differ from infections later in the pregnancy.ConclusionsOur results suggested that prenatal exposure to infection may be associated with lower levels of inflammatory markers among adult offspring. Additional prospective studies are needed to further explore this finding.

Abstract # 3089 Early life stress and vulnerability to viral infection in mood disorders

Early life stress (ELS) has negative sequelae, increasing the risk for mood disorders, medical illness, and inflammation in adulthood. However, its impact on vulnerability to infectious disease is largely unknown. Current stress and depression increase vulnerability to infection, begging the question of whether this association is driven by ELS. We addressed this question in a sample of volunteers with a DSM-IV diagnosis of a mood disorder (n = 262), and a replication sample of volunteers who met DSM-V criteria for a mood or anxiety disorder (n = 431). IgG antibodies to cytomegalovirus (CMV) and herpes simplex virus type 1 (HSV-1) were quantified by enzyme-linked immunosorbent assay. ELS was measured with the Childhood Trauma Questionnaire (CTQ). Logistic regression models controlling for age and sex revealed that for every point increase on the CTQ (total CTQ score with a possible range of 25–125) the odds of testing seropositive for CMV was increased by a factor of 1.01 (p = 0.062) in the discovery sample and a factor of 1.02 (p

Cumulative childhood risk is associated with a new measure of chronic inflammation in adulthood.

Childhood risk factors are associated with elevated inflammatory biomarkers in adulthood, but it is unknown whether these risk factors are associated with increased adult levels of the chronic inflammation marker soluble urokinase plasminogen activator receptor (suPAR). We aimed to test the hypothesis that childhood exposure to risk factors for adult disease is associated with elevated suPAR in adulthood and to compare suPAR with the oft-reported inflammatory biomarker C-reactive protein (CRP). Prospective study of a population-representative 1972-1973 birth cohort; the Dunedin Multidisciplinary Health and Development Study observed participants to age 38years. Main childhood predictors were poor health, socioeconomic disadvantage, adverse childhood experiences (ACEs), low IQ, and poor self-control. Main adult outcomes were adulthood inflammation measured as suPAR and high-sensitivity CRP (hsCRP). Participants with available plasma samples at age 38 were included (N=837, 50.5% male). suPAR (mean 2.40ng/ml; SD 0.91) was positively correlated with hsCRP (r 0.15, p<.001). After controlling for sex, body mass index (BMI), and smoking, children who experienced more ACEs, lower IQ, or had poorer self-control showed elevated adult suPAR. When the five childhood risks were aggregated into a Cumulative Childhood Risk index, and controlling for sex, BMI, and smoking, Cumulative Childhood Risk was associated with higher suPAR (b 0.10; SE 0.03; p=.002). Cumulative Childhood Risk predicted elevated suPAR, after controlling for hsCRP (b 0.18; SE 0.03; p<.001). Exposure to more childhood risk factors was associated with higher suPAR levels, independent of CRP. suPAR is a useful addition to studies connecting childhood risk to adult inflammatory burden.

LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis.

The Linear Ubiquitin chain Assembly Complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR11. Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, due to deregulation of TNFR1-mediated cell death2–8. In humans, deficiency in the third LUBAC component, HOIL-1, causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9–11. By creating HOIL-1-deficient mice, we here show that HOIL-1 is, however, as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is LUBAC’s catalytically active component, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1-signalling complex (TNFR1-SC), thereby preventing aberrant cell death. Both, HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of Caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- embryos, yet only combined loss of Caspase-8 with MLKL results in viable HOIL-1-deficient mice. Interestingly, Ripk3-/-Caspase-8-/-Hoil-1-/- embryos die at late-gestation due to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both, HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they unveil that, when LUBAC and Caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in foetal haematopoiesis.

Neonatal Colonic Inflammation Epigenetically Aggravates Epithelial Inflammatory Responses to Injury in Adult Life.

Background & AimsEarly life adversity is considered a risk factor for the development of gastrointestinal diseases, including inflammatory bowel disease. We hypothesized that early life colonic inflammation causes susceptibility to aggravated overexpression of interleukin (IL)1β.MethodsWe developed a 2-hit rat model in which neonatal inflammation (NI) and adult inflammation (AI) were induced by trinitrobenzene sulfonic acid.ResultsAggravated immune responses were observed in NI + AI rats, including a sustained up-regulation of IL1β and other cytokines. In parallel with exacerbated loss of inhibitor of kappa B alpha expression, NI + AI rats showed hyperacetylation of histone H4K12 and increased V-Rel Avian Reticuloendotheliosis Viral Oncogene Homolog A binding on the IL1B promoter, accompanied by high levels of norepinephrine/epinephrine. Propranolol, a β-blocker, markedly ameliorated the inflammatory response and IL1β overexpression by mitigating against epigenetic modifications. Adrenalectomy abrogated NI-induced disease susceptibility whereas yohimbine sensitized the epithelium for exacerbated immune response. The macrophages of NI rats produced more IL1β than controls after exposure to lipopolysaccharide (LPS), suggesting hypersensitization; incubation with LPS plus Foradil (Sigma, St. Louis, MO), a β2-agonist, induced a greater IL1β expression than LPS alone. Epinephrine and Foradil also exacerbated LPS-induced IL1β activation in human THP-1–derived macrophages, by increasing acetylated H4K12, and these increases were abrogated by propranolol.ConclusionsNI sensitizes the colon epithelium for exacerbated IL1β activation by increasing stress hormones that induce histone hyperacetylation, allowing greater access of nuclear factor-κB to the IL1B promoter and rendering the host susceptible to aggravated immune responses. Our findings suggest that β blockers have a therapeutic potential for inflammatory bowel disease susceptibility and establish a novel paradigm whereby NI induces epigenetic susceptibility to inflammatory bowel disease.