Literature Review: Microglial Activation and Cancer Induced Bone Pain

Microglial Development

Microglia are the resident macrophage-like cells of the central nervous system (CNS) and are the primary innate immune responders in a defense network that covers the entire brain parenchyma (Kettenmann, Hanisch, Noda, & Verkhratsky, 2011). They colonize the CNS during embryonic development from bone marrow derived hematopoietic stem cells that originate in the yolk sac and further proliferate to give rise to fully matured microglia (Alliot, Godin, & Pessac, 1999). This initial population of microglia within the CNS is referred to as resident microglia and they continue to invade the CNS during embryonic development until the blood brain barrier (BBB) is formed, after which they are never replenished (Milligan & Watkins, 2009; Matcovitch-Natan et al., 2016). Notably, the development of resident microglia is dependent upon the secreted cytokine, colony-stimulating factor 1, as it is known to regulate the proliferation, differentiation, and survival of hematopoietic stem cells (Elmore et al., 2014).

Following the formation of the BBB, self-renewal is the only source of new microglia in the healthy CNS (Matcovitch-Natan et al., 2016). These cells are referred to as perivascular microglia and are continually replenished in adulthood by bone marrow derived hematopoietic precursors (Milligan & Watkins, 2009). Although it remains a question of debate whether immune cells can cross the BBB, there is increasing evidence that bone marrow derived cells are capable of entering the CNS and differentiating into microglia in adults (Lull & Block, 2010). This has been shown to be possible even when the BBB remains intact, suggesting a mechanism for entry into the CNS. However, the mechanisms through which circulating cells are recruited to the CNS, and whether they enter the CNS under normal, resting conditions, are poorly understood (Lull & Block, 2010).

Resting Microglia and Microglial Activation

Phenotypically, in a healthy CNS, microglia are characterized by a ramified morphology consisting of small cell bodies with numerous slender branching processes. This is termed “resting microglia” and the immunological phenotype of this state is characterized by the low expression of major histocompatibility complex (MHC) proteins and other antigen-presenting surface receptors (Lull & Block, 2010). Despite being in a quiescent state, resting microglia have highly motile processes and are continually surveying the health of surrounding cells by constantly extending and retracting their processes, looking for changes in their microenvironment. Consequently, microglia have extensive signaling pathways whereby they can respond to extracellular signals, communicate with other cells including neurons and cells of the immune system, and maintain homeostasis (Kettenmann et al., 2011).

As microglia are considered to be the most susceptible sensors of brain pathology, the detection of any pathogens, signs of brain injury or nervous system dysfunction can cause microglia to undergo dramatic alterations in morphology (Kettenmann et al., 2011). This entails changing from “resting” ramified microglia into an amoeboid shape with short or nonexistent processes. This morphological change is also accompanied by changes in signaling and gene expression that result in changes in surface receptor expression, the release of proinflammatory factors such as tumor necrosis factor- (TNF-) α, Interleukin- (IL-) 1β, IL-12, reactive oxygen species (ROS), prostaglandins (PGs), chemokines and neurotoxic factors, among other substances such as glutamate (Lull & Block, 2010). The cumulative effect of these changes is a shift from “resting” to “activated” microglia.

Upon activation, microglia become phagocytic and seek to remove damaged cells and debris through phagocytosis (Kettenmann et al., 2011). The substances released by activated microglia further activate additional nearby astrocytes, microglia, and neurons to aid in this process, creating a positive feedback loop (Milligan & Watkins, 2009). Thus, once the harmful stimulus has been dealt with, it is imperative that the microglial inflammatory response be dampened and resolved. This is achieved by microglia releasing anti-inflammatory cytokines such as transforming growth factor-β, IL-4, and IL-10, and expression of Arginase-1(Lull & Block, 2010). These immunomodulatory mediators inhibit the release of proinflammatory factors from immune and nonimmune cells and promote tissue regeneration, thereby facilitating a return to homeostasis.

However, when the resolution phase of the inflammatory microglial response is altered, chronic microglial activation can ensue and results in a prolonged inflammatory response (Lull & Block, 2010). This can lead to tissue and neuronal damage and possibly cell death. It is for this reason that chronic microglial activation has ben implicated in the pathology of many neurodegenerative disorders such as Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, and AIDS (Lull & Block, 2010).

Microglial Glutamate Release