Microglia are cells of the immune system that reside in the central nervous system (CNS). They are the first line of defense against invading pathogens and play a vital role in maintaining neuronal homeostasis. Microglia surveil the CNS for changes in the extracellular environment and rapidly respond to any threats. They phagocytose debris and pathogens, produce cytokines and chemokines, and secrete neurotrophic factors that support neuronal survival and function. In addition, microglia modulate synaptic transmission and plasticity, making them key players in CNS development and function.
Microglia were first described by Rudolf Virchow in 1856 as “small globular cells” that were distinct from other cells of the nervous system. It was not until 1907 that these cells were shown to be of hematopoietic origin. Since then, much progress has been made in our understanding of microglial biology. We now know that microglia are derived from myeloid progenitors that enter the brain during embryonic development and differentiate into mature microglia upon arrival. Unlike other cell types of the immune system, microglia do not leave the CNS once they have colonized it. Instead, they remain resident throughout life, constantly monitoring their surroundings for signs of danger.
The ability of microglia to respond quickly to changes in their environment is largely due to their unique morphology. Unlike other macrophages, which have a rounded shape, microglia are highly ramified with long processes that extend far into tissue parenchyma. This allows them to rapidly detect changes in their surroundings through mechanosensation or direct contact with neurons. In addition, unlike other macrophages, microglia lack lysozymes— enzymes that break down bacterial cell walls—and instead rely on Toll-like receptors (TLRs) to recognize pathogens. TLRs are a family of evolutionarily conserved receptors that bind to specific molecular patterns associated with microbes (e.g., lipopolysaccharide [LPS] from Gram-negative bacteria). Binding of a TLR ligand triggers an intracellular signaling cascade that leads to activation of transcription factors and production of proinflammatory cytokines such as tumor necrosis factor (TNF) α and interleukin (IL)-1β . Activated microglia can also produce anti-inflammatory cytokines such as IL-10 and transforming growth factor β 1 (TGFβ1) .
In response to injury or disease,microglial activation results in an increase in cell size , upregulationof surface molecules involved in antigen presentation , releaseof reactive oxygen species , increased productionof proinflammatory cytokines , chemokines ,and neurotrophic factors , as well as enhanced phagocytic activity . Allof these changes help promote tissue repairand defend against invading pathogens . The precise timingand duration of this response is critical for proper tissue healing; too little or too muchactivation can resultin suboptimal outcomes . For example , early orexcessive proinflammatory responses have been linkedto poor outcomes following cerebral ischemiaz stroke . On the other hand , delayedor insufficient responses allow pathogensto proliferate uncheckedresultingin serious infections such asspongiform encephalopathies or neurodegenerative diseases like Alzheimer’sdisease(AD). Therefore ,a delicate balance must be maintainedbetween efficient clearanceof damaged tissue/pathogens while minimizing collateral damage tobenign cells . Thisis achieved through a complex series offeedback loops involving various soluble mediatorssuchas cytokinesthat regulatemicroglial activation state . Understandingthe intricate details offactorsthat drive this process will be crucialfor developing targeted therapeuticsaimed at manipulatingmicrobial status quo.”