Environmental triggers have important functions in multiple sclerosis (MS) susceptibility, phenotype, and trajectory. Exposure to early life trauma (ELT) has been associated with higher relapse rates in MS patients; however, the underlying mechanisms are not well-defined. Here we show ELT induces mechanistic and phenotypical alterations during experimental autoimmune encephalitis (EAE). ELT sustains downregulation of immune cell adrenergic receptors, which can be attributed to chronic norepinephrine circulation. ELT-subjected mice exhibit interferon-β resistance and neurodegeneration driven by lymphotoxin and CXCR2 involvement. These phenotypic changes are observed in control EAE mice treated with β1 adrenergic receptor antagonist. Conversely, β1 adrenergic receptor agonist treatment to ELT mice abrogates phenotype changes via restoration of immune cell β1 adrenergic receptor function. Our results indicate that ELT alters EAE phenotype via downregulation of β1 adrenergic signaling in immune cells. These results have implications for the effect of environmental factors in provoking disease heterogeneity and might enable prediction of long-term outcomes in MS.

Introduction: Elevated concentrations of inflammatory markers like C-reactive protein (CRP) can predict future development of obesity and cardiometabolic diseases. Elevated CRP levels are found in infancy in children born to mothers with maternal depression. Less is known about the intergenerational influence of maternal depression on offspring’s CRP profiles or its association with obesity risks in childhood, particularly in low-income Mexican populations. Methods: Cross-sectional data was collected from low-income Mexican mother-child dyads (n=43) living in central Mexico. Mothers completed the Patient Healthcare Questionnaire (PHQ-9) to screen for depression. Fasting dried blood spots, and body composition measurements through bioelectrical impedance were collected from both, child and mother. An enzyme-linked immunosorbent assay (ELISA) kit was used to measure CRP from dried blood spots. Moderated multiple regression and simple slopes were used in the analysis. Results: Mothers ranged in age from 21 to 45 (M=30.91±6.83). A total of 73% of mothers had overweight or obesity and 12% had elevated depressive symptoms (PHQ-9≥9). Mothers’ CRP values ranged from 0.08 to 9.05 mg/L (M= 2.15±2.00). Children were between the ages of 4 to 7 years old (M=4.86±0.91). Of children, 48% were male, 32% of children had overweight or obesity. Child CRP values ranged from 0.03 to 4.83 mg/L (M=.56±0.99). Child CRP was a significant predictor of children’s fat mass (β=0.51, p<0.001). A significant interaction between child CRP and maternal depression status was evident when regressed on the outcome of fat mass for children (β=0.54, p<0.02). Simple slopes of the interaction showed that, for children whose mothers have low depressive symptoms, child CRP values were positively associated with child fat mass (b=0.98; SE=0.38, p=0.01). For children whose mothers have severe depressive symptoms, child CRP values were negatively associated with children’s fat mass (β=-8.24; SE=4.02, p=0.048). Conclusion: Findings suggest that among children living with mothers with severe depressive symptoms, elevated CRP is associated with lower fat mass in children. Further investigation is needed to assess the biological pathways through which mother’s depression influences CRP in children.