Dysregulated neuronal–microglial cross-talk during aging, stress and inflammation

Abstract

Communication between neurons and microglia is essential for maintaining homeostasis in the central nervous system (CNS) during both physiological and inflammatory conditions. While microglial activation is necessary and beneficial in response to injury or disease, excessive or prolonged activation can have deleterious effects on brain function and behavior. To prevent inflammation-associated damage, microglia reactivity is actively modulated by neurons in the healthy brain. Age or stress-induced disruption of normal neuronal–microglial communication could lead to an aberrant central immune response when additional stressors are applied. Recent work suggests that both aging and stress shift the CNS microenvironment to a pro-inflammatory state characterized by increased microglial reactivity and a reduction in anti-inflammatory and immunoregulatory factors. This review will discuss how heightened neuroinflammation associated with aging and stress may be compounded by the concomitant loss of neuronally derived factors that control microglial activation, leaving the brain vulnerable to excessive inflammation and neurobehavioral complications upon subsequent immune challenge.

Introduction

The job of the immune system is to detect and eliminate invading pathogens as well as repair damage and maintain tissue homeostasis. Essential to an organism's survival, the brain must be protected, but the typical inflammatory response used to eliminate pathogens or support healing in peripheral tissues can be destructive in the central nervous system (CNS). Inflammation in the brain must be tightly controlled to preserve the viability of neurons that are, for the most part, non-regenerative (Galea et al., 2007). Although vulnerable, increasing evidence suggests that neurons are not the defenseless victims of excessive immune reaction, but rather are active players in CNS–immune interactions, carefully modulating mechanisms of microglial activation to maintain CNS integrity (Biber et al., 2007). However, recent findings suggest that processes as ubiquitous as aging and stress can compromise normal neuronal control of microglial reactivity, decreasing the brain's resiliency to potential inflammatory insult.

The main focus of this review is to discuss the potential mechanisms underlying dysregulated neuronal–microglial cross-talk during aging and stress-induced neuroinflammation. Following a brief introduction to key concepts including immune–brain communication and the essential role of microglia in the CNS innate immune response, we will highlight recent findings suggesting that both aging and stress can induce microglial “priming”, leading to an exaggerated and prolonged release of central cytokines upon additional immune stimulation. We then turn our focus on studies demonstrating that aging, stress and inflammation can impede neuronal regulatory mechanisms, including constitutively expressed immunomodulatory factors such as CD200 and CX3CL1 (fractalkine), which have been shown to play an important role in downregulating inflammatory processes. To conclude, we review evidence that aging and stress lead to deleterious alterations in the morphology and physiology of both neurons and microglia, and discuss how this concurrent decline in normal function can contribute to aberrant interactions under inflammatory conditions. Determining how neuroinflammatory processes can disrupt normal neuronal–microglia communication will contribute to a greater understanding of how microglial reactivity may be controlled or modulated following acute brain injury as well as during chronic neurological disease processes.