Persistent inflammatory states and their implications in brain disease

Purpose of review Apart from mental, motor and sensory functions, the human central nervous system (CNS) regulates a plethora of homeostatic (autonomic and hormonal) bodily functions. These functions are dependent on specialized neuronal networks. To ensure connectivity of these networks, they are continuously refined and supported by glial cells that outnumber neurons by, according to some accounts, an order of magnitude. Among glial cells, microglia - the brain resident macrophages - plays a crucial role in maintaining neuronal networks. However, in their concomitant role as brain immune cells microglia also engage in inflammatory signaling that may disrupt neuronal networks. Here, we review novel insights for molecular pathways involved in the protective functions of microglia and other immune cells in response to systemic signals and stimuli. Recent findings Recent evidence suggests that aging and systemic disease push individual microglia toward proinflammatory phenotypes compromising the connectivity of neuronal networks, resulting in neuropsychiatric disease. Furthermore, cells (self as well as the microbiome) outside the CNS have been shown to affect neuronal function. These recent findings have critical implications for mental health, particularly of an aging population, in particular for the development of novel immunomodulatory therapies for brain disease.