Microglia and Neurotoxicity

By Shane Daniel

“Any man who reads too much and uses his own brain too little falls into lazy habits of thinking”- Albert Einstein [6]. Einstein perfectly sums up the importance of the brain for cognitive functioning throughout our daily lives. Effective cognition results from an efficient functioning of the various molecular pathways in our brain. Let us focus on one molecular aspect of the brain- Microglia. Microglia are types of glial cells, which act as macrophages and are present throughout the Central Nervous System (CNS). These non-neuronal cells are responsible for the protection and support of neural activities. They are widely distributed throughout the brain and spinal cord and make up about 5-20% of glial cells within the CNS [1]. The two noteworthy features of the microglia are CNS maintenance and immune defense. An appropriate balance of microglial concentration is required to promote homeostasis of the CNS [1].

         The microglia detect the initial signs of pathogenic invasions and tissue damage in the CNS, which is also shielded by the blood-brain barrier. These cells also play a significant role in tissue repair and remodeling after a potential damage has incurred in the CNS. Unfortunately, unregulated microglial activation leads to inflammation which is observed in almost all brain pathologies. This observation suggests that microglia has a direct effect on neurons and promotes the progression of diseases [1].

During events of neuronal stress or injury, these cells quickly react and tend to modify their phenotype, causing a detrimental variety of microglial activation, which is quite often connected to neuroinflammation and neurotoxicity in many neuropathological conditions [2]. Researchers have determined the existence of a mechanism which triggers this type of microglial activation which leads to necrotic neural damage [2]. Necrosis is a type of unprogrammed cell death in which the destroyed debris tends to contaminate neighboring cells. Therefore, a necrotic damage of neurons certainly poses as a hazard in the CNS.

Researchers have furthered determined that necrotic-like neuronal death is related to the occurrence of various pathological conditions such as cerebral ischemia, meningitis, HIV-related dementia, cerebral malaria, and other noninfectious-related neuroinflammation like multiple sclerosis. In such pathological states, the proliferation of microglia contributes to increased neurotoxicity [2].

In order for the body to detect pathogens, the immune system is equipped with receptors on the cell surface called Pattern Recognition Receptors (PRRs) which specialized in the recognition of specific pathogens that invade the body [3]. An increasing amount of evidence suggests that “danger signals” that are released by necrotic cells, can be detected by the PRR on macrophages. MyD88 is an adaptor protein that is present in the TLR (a type of PRR) and is required for signal transduction which helps to track down the pathogens. Due to the presence of this adaptor protein, microglial cells are triggered to be activated [2]. An experiment using mice was performed to confirm the dependence microglial cells had on MyD88. When the MyD88 protein was ablated from microglia cells, this subdued the activation of microglia by necrotic neurons. The results revealed that necrotic neurons are most likely detected by the MyD88 TLR on microglia and triggers the expression of pro-inflammatory genes that are related to microglia activation [2].

The phylogeny of microglia suggests that its existence has been primitive; as even invertebrate creatures, such as: leech, snails, arthropods, crustaceans and others contain microglia cells [4]. Few research studies have highlighted the similarities between the microglia that are present in vertebrates and invertebrates. Studies on the leech have found that each of their body ganglia contains about 400 neurons and 10,000 microglia; and that this significant ratio greatly benefits the leech in nervous tissue repair and regeneration capabilities [4].

A research team from University of South Florida (Tampa), and Fujian University of Traditional Chinese Medicine (Fuzhou) has investigated the role Acupuncture plays on the body [5]. With past information of how microglia cells act as a macrophage at damaged central nervous tissues sites, they further explored the relation between acupuncture and pain. They discovered that acupuncture inhibits the proliferation of microglia cells, and it also improved functional recovery after a Spinal Cord Injury (SCI). Therefore, they concluded that Acupuncture acts as an analgesia on SCI by inhibiting the activation of microglia cells [5].

The advantages, disadvantages, ontogeny, phylogeny, and other additional aspects of microglia are yet to be discovered. This cell plays a key role in neurology, and the overall health of many organisms that we observe in the phylogenetic tree.

Works Cited

  • Pais, Teresa F, et al. “Necrotic Neurons Enhance Microglial Neurotoxicity through Induction of Glutaminase by a MyD88-Dependent Pathway.” Journal of Neuroinflammation, BioMed Central, 9 Oct. 2008, jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-5-43.
  • Zaru, Rossana. “Pattern Recognition Receptors.” British Society for Immunology, British Society for Immunology, www.immunology.org/public-information/bitesized-immunology/receptors-and-molecules/pattern-recognition-receptors.
  • Biber, K, et al. “What Is Microglia Neurotoxicity (Not)?” , U.S. National Library of Medicine, June 2014, www.ncbi.nlm.nih.gov/pubmed/24590682.