Microglia cells represent, depending on the species, from 5% to 20% of the glial cells in the adult brain. It is commonly accepted that microglia precursors originate in the yolk sac – as the tissue specific macrophages – although their identity has not been confirmed so far. Once the development of the blood-brain barrier is complete, the microglia acts as an autonomous immune system inside the brain, as the blood-brain barrier almost does not allow any interchange with the blood cells.

So, microglial cells activate themselves in case, for example, of a virus infection, triggering an inflammatory or anti-inflammatory response depending on the specific situation. Moreover, microglia has a phagocytic activity that removes damaged cells or tissue debris, thus being similar to macrophages.

The M1 and M2 microglia states: from inflammation to wound healing

In normal conditions, microglial cells are in a quiescent state and monitor the brain environment. When an infection or an injury occurs, they shift to an activate state, called M1, in which their membrane receptors recognize the exogenous antigens and release cytokines, a wide class of small proteins that cause an inflammatory response. This system helps, for example, to identify antigens as the lipopolysaccharide (a molecule specific of the Gram-negative bacteria), to “sweep” the rests of died cells, or to begin the repair of the tissues after an injury.

In any case, the inflammation needs to be controlled, otherwise, the same neurons are damaged. For this reason, after having triggered the inflammatory response, the microglia shifts to an alternative activate state, called M2, that limits the immune response and helps to repair the cells impaired by the immune response.

Phagocytosis and cytokines release

Microglial cells have many different receptors on their membrane surfaces, each of them with high affinity for specific antigens coming from infective agents or dead/apoptotic brain cells. The class of TLR receptors and the TREM2 receptors are the most important among the ones involved in the phagocytosis mechanisms. Their correct functionality is also tightly related to the onset of some neuropathologies.

TLR receptors recognize molecules typical of microbial pathogens, so that, when the brain is infected, microglial cells activate and “eat” the exogenous cells. TREM2 receptors activate in presence of apoptotic cells by removing their rests and at the same time blocking the release of the inflammatory molecules. Healthy neurons have their own defense systems to avoid being phagocytized by the activated microglia: their membrane surface presents specific modified proteins that give the microglial cells the signal to not eat them.

The production of cytokines is important for many functions, from the cellular communication to the immune response, from the regulation of the inflammation to the growth and differentiation of the cells. Microglia release inflammatory cytokines in response to microbial infections, or injuries, or stroke. At the same time, other cytokines have an anti-inflammatory effect that counterbalances the cell damages caused by the inflammation.

So, the microglia constantly checks the equilibrium of the brain environment by balancing inflammatory and anti-inflammatory mechanisms in order to maintain the brain homeostasis.

“Non-conventional” activity of the microglia

During the last years, new studies have focused on other roles of the microglial cells. For example, they participate in the postnatal development of the brain by phagocyting the excess of neurons produced during the development of the Central Nervous System. In the vertebrates, half of the neurons is removed in order to guarantee the correct growth of the brain.

Microglia also participates in the maturation of the synapses, in fact, microglial cells cover and eliminate some synapses during the brain development. This process, also known as pruning, as it resembles the cut of tree branches, is not well understood at the molecular level yet.

Role of the microglia in the neurological diseases

As the microglia participates in a lot of processes, including the postnatal development of the brain, its link with neurological diseases appear to be obvious. Indeed, the role of microglia has been demonstrated in various diseases.

The Nasu-Hakola Disease (NHD) is caused by genetic mutations of the microglial cell receptors DAP1 or TREM2. The patients develop personality changes and memory impairment that leads to dementia and the death. At the molecular level, the lack of functionality of TREM2 causes the accumulation of the rests of the apoptotic cells that cannot be removed. This triggers a continuous inflammatory response that leads to the degeneration of the neurons.

The cause of the Rett syndrome (RTT) is a mutation in the gene MECP2. Recent studies, however, have demonstrated that the microglia has a lower capability to remove the rests of the apoptotic cells, thus contributing to maintaining the RTT. Contrary to NHD, in this case, there is no increase of inflammation.

A role of the microglia has been also hypothesized for the Tourette syndrome. In this case, microglia could fail during the pruning of the synapses of the growing neurons. Other studies have highlighted a possible involvement of the microglia in the autistic spectrum disorders, by thinking in a relationship between the development of the neurons and the immune cells.


The impairment of the microglia during the first years of life could imply serious damages for the developing brain. Some diseases, as the NHD, can be considered as primary microgliopathies, while in other diseases the microglia is involved with other genetic and environmental factors. Both the presence of inflammation in the brain and the inactivity of the microglia can be taken in consideration as markers of neurodegenerative diseases.



Arcuri C. et al. The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS. Front. Mol. Neurosci., 19 June 2017 |




The elaboration of this post has been financed by the project PI15/01082, as a part of the National Plan of I+D+I and co-financed by the ISCIII – General Deputy Direction for Evaluation and Development of Health Research – and the European Regional Development Fund (ERDF).