Microglial expression of MHCII, a marker of microglial activation, is increased in the aged but otherwise healthy brain of humans, non-human primates and rodents (Frank, et al., 2006a,Godbout, et al., 2005,Perry, et al., 1993,Sheffield and Berman, 1998,Streit and Sparks, 1997). 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 organisms 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 brains 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 Panulisib (P7170, AK151761) 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 Panulisib (P7170, AK151761) 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 Panulisib (P7170, AK151761) 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. == THE NEUROIMMUNE RESPONSE == == Immune-Brain Communication Mouse monoclonal to APOA4 == The bi-directional communication between the immune system and central nervous system (CNS) is critical for mounting an appropriate immunological, physiological and behavioral response to infection and injury. The hosts first line of defense is the innate immune system. Innate immune cells, including macrophages in the periphery, and microglial cells in the CNS, detect potential insults via pattern-recognition receptors (PRRs) which recognize and respond to infectious elements (pathogen-associated molecular patterns, PAMPs), as well as endogenous danger signals induced by tissue damage (danger-associated molecular patterns, DAMPs) (Akira, et al., 2006,Matzinger, 2002). Upon activation, cells of the innate immune system synthesize and release cytokines such as interleukin (IL)-1, IL-6 and tumor necrosis factor- (TNF-) that serve as major mediators of the immune response. Peripheral cytokines induced by the innate immune system act on the brain to induce nonspecific symptoms of infection including lethargy, listlessness, decreased activity and loss of interest in social Panulisib (P7170, AK151761) interaction (Kelley, et al., 2003). This aspect of host defense has been termed the sickness response and includes changes in body temperature, increased sleep, reduction in food and water intake, and activation of the hypothalamic-pituitary-adrenal (HPA) axis (Dantzer and Kelley, 2007,Maier and Watkins, 1998). The physiological and behavioral aspects of the sickness response reflect the expression of an adaptive motivational state that resets the organisms priorities to promote resistance to pathogens and recovery from infection (Dantzer, 2001,Hart, 1988,Johnson, 2002). To induce a behavioral Panulisib (P7170, AK151761) response, peripheral cytokines need to be able to exert their effects in the brain. Cytokines can access the brain via active transport mechanisms or diffusion at circumventricular organs (CVOs) where blood vessels lack a functional blood-brain barrier (Banks, et al., 2002,Konsman, et al., 1999). In addition, peripheral cytokines do not need to gain direct entry into the CNS because they can act at the blood-brain barrier to induce the synthesis and release of inflammatory mediators (cytokines and.
