Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration

Abstract

Microglia, the resident immune cells of the central nervous system (CNS), play an important role in CNS homeostasis during development, adulthood and ageing. Their phenotype and function have been widely studied, but most studies have focused on their local interactions in the CNS. Microglia are derived from a particular developmental niche, are long-lived, locally replaced and form a significant part of the communication route between the peripheral immune system and the CNS; all these components of microglia biology contribute to maintaining homeostasis. Microglia function is tightly regulated by the CNS microenvironment, and increasing evidence suggests that disturbances, such as neurodegeneration and ageing, can have profound consequences for microglial phenotype and function. We describe the possible biological mechanisms underlying the altered threshold for microglial activation, also known as ‘microglial priming’, seen in CNS disease and ageing and consider how priming may contribute to turning immune-to-brain communication from a homeostatic pathway into a maladaptive response that contributes to symptoms and progression of diseases of the CNS.

Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB1–AMPK signaling pathway

“…Microglial cells play critical roles in immune surveillance and host defense by acting as the prime resident innate‐immune cells in the central nervous system (CNS; Perry & Holmes, 2014; Salter & Beggs, 2014). Under normal conditions, microglial cells not only provide surveillance of the CNS environment but also respond to danger signals (Crotti & Ransohoff, 2016; Perry & Teeling, 2013). Activated microglial cells undergo morphological transformation (increase in the size of cell bodies and thickness of proximal processes and decreased ramification of distal branches; Plastira et al., 2016; Walker et al., 2014) and secrete pro‐inflammatory cytokines, leading to self‐perpetuating damage to the neurons, also known as the classically activated M1 phenotype.…”

Antimalarial Drug Artemether Inhibits Neuroinflammation in BV2 Microglia Through Nrf2-Dependent Mechanisms

“…Under normal conditions, these cells provide surveillance whilst maintaining homeostasis in the brain [2]. In response to injury, harmful toxins, infection or inflammation, microglial cells become activated, secreting pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), reactive oxygen/nitrogen species and pro-inflammatory cytokines including IL-6 and TNFα [3,4].…”

“…Excessive production of pro-inflammatory mediators generated during neuroinflammation can damage neighbouring neurons, and further activate the microglia, as well as other glia cells resulting in a self-perpetuating cycle [2,4,9].…”

“…NF-κB binds to the DNA and its transcriptional activity regulates several genes, which promote neuroinflammation. The p38 mitogenactivated protein kinase (p38 MAPK) signalling pathway also plays an important role in the expression and activity of pro-inflammatory cytokines in microglial cells [6][7][8].Excessive production of pro-inflammatory mediators generated during neuroinflammation can damage neighbouring neurons, and further activate the microglia, as well as other glia cells resulting in a self-perpetuating cycle [2,4,9].Furthermore, activation of the microglia and the resulting neuroinflammation play a critical role in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (AD) [10]. Consequently, pharmacological modulation of pro-inflammatory mediators generated by the microglia during chronic inflammation and modulation of the signalling pathways responsible for their production is an important target in treating severe neuroinflammatory disorders.…”

Characterization of Inflammatory Gene Expression and Chemotaxis of Macrophages Expressing Guanylin and Guanylyl Cyclase-C

“…Macrophages are highly heterogeneous cells found in nearly all tissues of the body [3][4][5] and can exhibit at least two different phenotypes: the classically activated M1 phenotype and the alternatively activated M2 phenotype [6,7]. CD11c-positive M1 macrophages are characterized by high expression of proinflammatory cytokines such as interleukin (IL) 1β, IL-6, tumor necrosis factor α (TNF-α), and monocyte chemoattractant protein (MCP) 1 [8], which are involved in inflammation in tissues [9][10][11][12]. In contrast, mannose receptor CD206-positive M2 macrophages are characterized by high expression of anti-inflammatory cytokines such as IL-10 [13,14] and arginase (Arg) 1 [15,16], which are involved in the repair or remodeling of tissues [4,9,17].…”