Structural and functional connections between the autonomic nervous system, hypothalamic–pituitary–adrenal axis, and the immune system: a context and time dependent stress response network

The autonomic nervous system (ANS), hypothalamic–pituitary–adrenal (HPA) axis, and immune system are connected anatomically and functionally. These three systems coordinate the central and peripheral response to perceived and systemic stress signals. Both the parasympathetic and sympathetic components of the autonomic nervous system rapidly respond to stress signals, while the hypothalamic–pituitary–adrenal axis and immune system have delayed but prolonged actions. In vitro, animal, and human studies have demonstrated consistent anti-inflammatory effects of parasympathetic activity. In contrast, sympathetic activity exerts context-dependent effects on immune signaling and has been associated with both increased and decreased inflammation. The location of sympathetic action, adrenergic receptor subtype, and timing of activity in relation to disease progression all influence the ultimate impact on immune signaling. This article reviews the brain circuitry, peripheral connections, and chemical messengers that enable communication between the ANS, HPA axis, and immune system. We describe findings of in vitro and animal studies that challenge the immune system with lipopolysaccharide. Next, neuroimmune connections in animal models of chronic inflammatory disease are reviewed. Finally, we discuss how a greater understanding of the ANS-HPA-immune network may lead to the development of novel therapeutic strategies that are focused on modulation of the sympathetic and parasympathetic nervous system.