If you ask anyone about the brain, their response will almost certainly involve neurons. Although neurons have been the stars of neuroscience for the past hundred years, the brain would be entirely dysfunctional if not for the variety of brain support cells, collectively known as glia.1

Glial cells serve a variety of purposes in the central nervous system. Oligodendrocytes produce an insulating fatty-material called myelin, and astrocytes maintain electrical impulses in the neuronal network.1 Perhaps the least glorious of glial functions are carried out by the microglia, which are the neurological equivalent of your household gardeners: pruning unwanted synapses and tending to the new ones. However, microglia are the first line of immune defense in the brain. From the brain’s humble beginnings as a mass of undifferentiated neurons to its affliction with the weeds of old age, microglia are tasked with neuronal maintenance and repair, meaning that deviation from their “just-right” activity can cause a variety of neural diseases. Too little activity, and one can be autistic or schizophrenic; too much activity, and one may be afflicted with Alzheimer’s or Parkinson’s. Given the large role these tiny cells play in brain protection, therapies that regulate microglial activation could be the key to curing a slew of neurological disorders.

Microglia respond to neural stress and injury through different mechanisms unique to their respective cell types: amoeboid phagocytic, resting ramified, and activated.2 Amoeboid phagocytic glia act similarly to other scavengers and ingest large amounts of cellular debris in the developing brain during gestation.3 In postnatal development, these glia transform into resting ramified glia, which remain semi-dormant until their extended branches are activated by electrical signals from neurons or the presence of harmful substances.4 Activated microglia can secrete a variety of anti-inflammatory chemicals to prevent neurological problems, such as brains tumors and axonal injury.5 Microglia can also increase the permeability of the blood-brain barrier, allowing bodily immune cells to assist with brain immune defense.2 A negative feedback mechanism in microglia regulates their own immune response as well as that of other helper immune cells.

In most pathologies, microglia experience a change in their normal activity caused by environmental factors.2 Gliomas, or tumors in the neural glial tissues, are diseases that microglia should be able to handle. However, cells from the two microglial subcategories that migrate toward gliomal cells, M1 and M2, react differently in the gliomal microenvironment. M1 microglia promote tumor degradation by activating other immune cells and phagocytizing gliomal tumor cells. However, M2 microglia promote tumor growth by inhibiting proinflammatory cytokine activity and slowing immune cell responses.6 Cytokines are small proteins that aid cell communication and regulate cellular immune response.7 Additionally, tumor necrosis factor (TNF) stimulates inactivated microglial migration into the glioma, carving a pathway for glioma to migrate to other areas of the brain. Some gliomal therapies have focused on inhibiting the activity of M2 microglia. Various drug treatments that inhibit M2 activity have been shown to decrease gliomal proliferation in vivo. However, the success of these therapies should be treated with caution: gliomal immunosuppression both inactivates multiple immune responses outside of microglia and has the plasticity to circumvent anti-tumor therapies.6

Reduced microglial activity is related to a variety of neurodevelopmental disorders such as autism that demonstrate decreased connectivity in the brain.8 Microglia are responsible for forming mature spines and eliminating immature connections in the brain during post-natal development. This seems counterintuitive; how can decreasing in microglial activity, which causes less synaptic pruning, somehow cause less connectivity in the brain? Reduced microglial activity is actually preventing the brain from eliminating immature spine connections, which leads to fewer mature connections. Failing to eliminate immature connections physically hinders other synapses from forming multiple connections. Techniques that would increase microglial activity include increasing CR3/C3 pathway activity, which triggers synaptic pruning via an unknown mechanism.9 Although microglial therapies might not entirely eliminate autism, which acts through a variety of known and unknown neurological mechanisms, there is potential for ameliorating some symptoms.

Microglia often experience increased sensitivity in the aging brain caused by an increased expression of activation markers.10 This leads to several inflammatory neurological illnesses, including Alzheimer’s disease (AD). Microglia are once again found to play contradicting roles in the progression of Alzheimer’s; their activity is critical in producing neuroprotective anti-inflammatory cytokines, removing cell debris, and degrading amyloid-β protein, the main component of amyloid plaques that cause neurofibrillary tangles.10 Alternatively, activating microglia runs the risk of hyper-reactivity, which can cause extreme detriment to the central nervous system. Non-steroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease the amount of activated microglia by 33% in non-AD patients. Treatment on microglial cultures increased amyloid-β phagocytosis and decreased inflammatory cytokine secretion. However, this treatment did not alter the microglial inflammatory activity in AD patients. The ideal microglial therapy for neuroinflammatory illnesses would result in the expression of only positive microglial activity, such as amyloid-β degradation, and the elimination of negative activity, such as pro-inflammatory secretion. One mechanism that increases pro-inflammatory secretion is amyloid-β binding to formyl peptide receptor (FPR) on microglia. Protein Annexin A1 (ANXA1) binding to FPR has been seen to inhibit interactions between amyloid-β and FPR, which decreases pro-inflammatory secretion.

Central nervous system pathology researchers often speculate as to how certain bacteria and viruses are able to enter the brain and consider mechanisms such as increase in blood-brain barrier permeability and chemical exchange through cerebrospinal fluid. However, the discovery of nervous system lymphatic vessels may put much of this speculation to rest and open up an entirely new venue of neuroimmunological research.11 The interaction between microglial immune function and these lymphatic vessels could introduce treatments that recruit microglia to sites where bacterial and viral infections are introduced into the brain. Alternatively, therapies that increase bodily immune cell and microglial interactions by increasing the presence of bodily immune cells in the brain could boost the neural immune defense. Other approaches could involve introducing drugs that increase or decrease microglial-activity into more accessible lymphatic vessels elsewhere in the body for proactive treatment of neonatal brain diseases. Although we have made some steps towards curing brain diseases that involve microglial activity, coordinating these treatments with others that increase neural immune defenses has the potential to create effective treatment for those afflicted by devastating and currently incurable neurological diseases.

References

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