Stress and brain immunity: Microglial homeostasis through hypothalamus-pituitary-adrenal gland axis and sympathetic nervous system

Stress has been well documented to bring about various clinical disorders, ranging from neurodegeneration, such as Parkinson's (PD) and Alzheimer's diseases (AD), to metabolic disorders including diabetes mellitus. Importantly, microglia, immunocompetent cells in the brain, have been shown to be involved in these clinical disorders. In the recent studies aiming to clarify the microglial responses, microglia are found to be quite responsive to stressful events, such as acute, subchronic, chronic stress, and social defeat stress. However, the mechanisms of these stress response on microglial activation have been not fully understood. In response to stress exposure, both the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system (SNS) are simultaneously activated, with the former inducing glucocorticoids (GCs) and the latter noradrenaline (NA), respectively. However, the effects of these stress-induced GCs and NA have not been consistent. The GCs, conventionally known to act on microglia as immunosuppressant, is also reported to act on it as stimulator. Similarly, the NA has been reported to act on microglia as stimulator or inhibitor depending on environmental conditions. Since any kinds of stress upregulate the HPA axis and SNS, with the levels of upregulation variable depending on the stress type, it is plausible that microglia is closely regulated by these two stress pathways. In this review, we discuss the microglial responses induced by various stresses as well as the possible mechanism by which stress induces microglial activation.