Altering the Polarization of Microglia for Therapeutic Benefit

In past years, researchers have established that the immune cells known as macrophages are involved in wound healing, and are split into groups with different polarizations (M1 and M2) that play different roles in this process. Adjusting the balance between the numbers in each group may enhance regeneration, and a disarray in this balance of numbers appears to take place over the course of aging, perhaps contributing to the decline in regenerative capacity. This polarization and its consequences exist for microglia as well, the predominant immune cell in the brain. These cells are responsible for a great many tasks beyond those of immune cells elsewhere in the body; not just clearing debris and pathogens, but also deeply involved in the correct function of connections between brain cells, for example. In this paper, researchers discuss the potential to obtain therapeutic benefits through adjusting the balance of polarization types in the microglial population.

Microglia, the resident immune cells of the central nervous system (CNS), are highly specialized macrophages that play a fundamental role in neurodegenerative diseases. Microglia have been traditionally classified as either of the following: (1) resting with branched morphology and present in healthy brains or (2) activated with amoeboid morphology and present in diseased brains. Recent microglia classifications are more complex. Activated microglia are now recognized as being heterogeneous and plastic, and exist in various phenotypes in the CNS. Microglia can be divided into at least two types (neurotoxic or neuroprotective) based on their function. Microglia can promote neurotoxicity via the release of several pro-inflammatory mediators, such as nitric oxide, interleukin (IL)-1β, and tumor necrosis factor-alpha (TNF-α). Conversely, they can be neuroprotective and neurosupportive, via several mechanisms under certain conditions. For example, neuroprotective roles of microglia include glutamate uptake, removal of dead cell debris and abnormally accumulated proteins, and production of neurotrophic factors.

The dual nature of microglial functional polarization is consistent with the general classification of macrophages as being either the M1 (classic pro-inflammatory) or M2 (anti-inflammatory) phenotype. Specific environmental cues induce macrophages to adopt a given functionality. For example, stimulation with either lipopolysaccharide (LPS) or interferon (IFN)-γ induces activation of the classical M1 phenotype, whereas stimulation with either IL-4 or IL-13 induces the M2 activation. Microglia are critical to immune response in the CNS, and unsurprisingly, microglial functional polarization has been implicated in almost all CNS disorders, and in the progression of neurodegenerative diseases. Microglia also play key functional roles in recovery from brain injury and in the maintenance of homeostasis in the brain.

Although the specific classification of M1 and M2 functionally polarized microglia remains a topic for debate, the use of functional modulators of microglial phenotypes as potential therapeutic approaches for the treatment of neurodegenerative diseases has garnered considerable attention. The modulation of microglial polarization toward the M2 phenotype may lead to development of future therapeutic and preventive strategies for neuroinflammatory and neurodegenerative diseases.



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