Childhood trauma and LPS-stimulated inflammation in adulthood: Results from the Netherlands Study of Depression and Anxiety

Background: Childhood trauma (CT) is robustly associated with psychiatric disorders including major depressive and anxiety disorders across the life span. The innate immune system may play a role in the relation between CT and stress-related psychopathology. However, whether CT influences the innate production capacity of cytokine levels following ex vivo stimulation by lipopolysaccharide (LPS), is currently unknown. Methods: Using data from the Netherlands Study of Depression and Anxiety (NESDA, n=1237), we examined whether CT (emotional neglect, emotional, physical, and sexual abuse before the age of 16), assessed by the Childhood Trauma Interview, was associated with levels in supernatants of interferon (IFN)γ, interleukin-2 (IL-2), IL-4, IL-6, IL-8, IL-10, IL-18, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein (MIP)-1α, MIP-1β, matrix metalloproteinase-2 (MMP-2), TNFα and TNFβ after ex vivo stimulation with LPS. Cytokines were analysed individually and cumulatively (overall inflammation index and number of cytokines in high-risk quartile (HRQ)) using linear regression analyses. Results: After adjustment for demographic, lifestyle, and health-related covariates, total CT severity was associated with the overall inflammation index (β = 0.085, PFDR = 0.011), the number of cytokines in HRQ (β = 0.063, PFDR = 0.036), and individual markers of IL-2 (β = 0.067, PFDR = 0.036), IL-6 (β = 0.091 PFDR = 0.011), IL-8 (β = 0.085 PFDR = 0.011), IL-10 (β = 0.094 PFDR = 0.011), MCP-1 (β = 0.081 PFDR = 0.011), MIP-1α (β = 0.061 PFDR = 0.047), MIP1-β (β = 0.077 PFDR = 0.016), MMP-2 (β = 0.070 PFDR = 0.027), and TNFβ (β = 0.078 PFDR = 0.016). Associations were strongest for individuals with severe CT, reporting multiple types or higher frequencies of trauma. Half of the findings persisted after adjustment for psychiatric status. The findings were consistent across different CT types. Conclusion: Childhood Trauma is associated with increased LPS-stimulated cytokine levels, with evidence for a dose-response relationship. Our results highlight a dysregulated innate immune system capacity in adults with CT, which could contribute to an increased vulnerability for psychopathology and somatic disorders across the lifespan.