Childhood adversity has been repeatedly and robustly linked to physical and mental illness across the lifespan. Yet, the biological pathways through which this occurs remain unclear. Functioning of the inflammatory arm of the immune system and the hypothalamic-pituitary-adrenal (HPA)-axis are both hypothesized pathways through which childhood adversity leads to disease. This review provides a novel developmental framework for examining the role of adversity type and timing in inflammatory and HPA-axis functioning. In particular, we identify elements of childhood adversity that are salient to the developing organism: physical threat, disrupted caregiving, and unpredictable environmental conditions. We propose that existing, well-characterized animal models may be useful in differentiating the effects of these adversity elements and review both the animal and human literature that supports these ideas. To support these hypotheses, we also provide a detailed description of the development and structure of both the HPA-axis and the inflammatory arm of the immune system, as well as recent methodological advances in their measurement. Recommendations for future basic, developmental, translational, and clinical research are discussed.

This study provides a comprehensive review of the published research on the association between early life adversity and markers of inflammation in children and adolescents. We conducted a systematic review of the published literature on the association between early life adversity and markers of inflammation in pediatric populations. To date, 27 studies have been published in this area representing a wide range of global populations and diverse methods of which nearly half were prospective, longitudinal studies. Of these 27, only 13 studies shared an inflammatory outcome with 4 or more other studies; 9 for CRP, and 7 for IL-6. The association between early life adversity and both CRP, z = 0.06 [−0.01, 0.14], and IL-6, z = 0.06 [−0.17, 0.30], was small and nonsignificant when subjected to meta-analysis, although comparable in magnitude to the effects observed in adult samples. Descriptively, the association between early life adversity and CRP appeared to be stronger in studies conducted in infants and adolescents compared with middle childhood. There was minimal evidence of publication bias for studies measuring CRP, but evidence of publication bias for studies using IL-6. Eight studies have looked at the association between early life adversity and stimulated inflammatory cytokines in vitro, and both the methods and results of these studies were mixed; the majority observed exaggerated production of inflammatory cytokines despite mixed methodological approaches that make comparisons across studies difficult. In summary, the evidence supporting an association between early life adversity and inflammation in pediatric samples is limited so far by the number of studies and their heterogeneous methodological approaches. More research that is grounded in a developmental framework and informed by the complexity of the innate immune system is needed in this area.

A wealth of evidence has implicated inflammation in the development of depression. Yet, the heterogeneous nature of depression has impeded efforts to understand, prevent, and treat the disease. The purpose of this integrative review is to summarize the connections between inflammation and established core features of depression that exhibit more homogeneity than the syndrome itself: exaggerated reactivity to negative information, altered reward processing, decreased cognitive control, and somatic syndrome. For each core feature, we first provide a brief overview of its relevance to depression and neurobiological underpinnings, and then review evidence investigating a potential role of inflammation. We focus primarily on findings from experimental paradigms of exogenously-induced inflammation. We conclude that inflammation likely plays a role in exaggerated reactivity to negative information, altered reward reactivity, and somatic symptoms. There is less evidence supporting an effect of inflammation on cognitive control as assessed by standard neuropsychological measures. Finally, we discuss implications for future research and recommendationsfor how to test the role of inflammation in the pathogenesis of heterogeneous psychiatric disorders.