Microglia Shape Brain Inflammation and Open New Therapeutic Avenues

Microglia, the resident immune cells of the central nervous system, play a key role in maintaining brain balance. Long considered mere bystanders, they are now recognized as dynamic actors capable of continuously monitoring the brain environment and rapidly responding to injuries or infections. Their remarkable plasticity allows them to adopt opposing roles—sometimes protective, sometimes toxic—depending on the context of inflammation or neurodegenerative disease.

These cells do not operate in isolation. They interact with neurons, astrocytes, oligodendrocytes, and even peripheral immune cells to regulate essential processes such as the elimination of unnecessary synapses, the amplification of inflammation, or the repair of the myelin sheath. Their central position in these networks places them at the heart of neuroinflammation mechanisms, a phenomenon involved in a wide range of diseases, including multiple sclerosis, Alzheimer’s disease, and Parkinson’s disease.

Recent advances, particularly through single-cell sequencing, have revealed an unsuspected diversity of microglia. They can adopt various states, such as disease-associated microglia, which are characterized by an increased ability to clear cellular debris or toxic protein aggregates. These states are not fixed: microglia adapt based on the signals they receive, shifting from a protective profile to an inflammatory one if the aggression persists. For example, in Alzheimer’s disease, they can help eliminate amyloid plaques, but their prolonged activation can also worsen neuronal damage.

Their origin is equally fascinating. Unlike most other macrophages in the body, microglia do not originate from the bone marrow but from precursors derived from the yolk sac, an embryonic structure. From the earliest stages of development, these precursors migrate to the brain, where they differentiate into mature microglia. This discovery has revolutionized the understanding of their biology and opened the way to new strategies for specifically targeting these cells without affecting other immune populations.

Microglia communicate with their environment through a repertoire of surface receptors capable of detecting various signals, such as chemokines, cytokines, or purinergic molecules. These interactions allow them to modulate their activity based on the brain’s needs. For example, in the event of injury, neurons release ATP, which activates microglia via purinergic receptors, triggering an inflammatory response. Conversely, inhibitory signals, such as the CD200 protein, keep microglia in a resting state to prevent excessive inflammation.

Their role in synapse elimination is particularly important. During brain development, microglia remove superfluous or dysfunctional neuronal connections, a process known as synaptic pruning. This mechanism, essential for the maturation of neuronal circuits, partly relies on the complement system, a cascade of proteins that mark synapses for elimination. However, dysfunction in this process can lead to excessive synapse elimination, as observed in certain neurodegenerative or psychiatric diseases, such as schizophrenia.

Microglia also interact closely with astrocytes, another population of glial cells. Together, they regulate synaptic homeostasis and the inflammatory response. For example, astrocytes can secrete molecules that activate microglia, which in turn release pro-inflammatory cytokines. This feedback loop can amplify inflammation and contribute to the progression of diseases such as multiple sclerosis. Conversely, in certain contexts, microglia can secrete anti-inflammatory factors that limit astrocyte activation, thereby promoting the resolution of inflammation.

Their interaction with oligodendrocytes, the cells responsible for myelin production, is equally crucial. In diseases like multiple sclerosis, activated microglia can phagocytose damaged myelin, but excessive activation can worsen lesions. Recent studies have shown that microglia can also secrete factors that promote myelin repair, highlighting their dual role in these processes.

Finally, microglia interact with T lymphocytes, adaptive immune cells. In cases of chronic inflammation or neurodegenerative disease, activated microglia secrete chemokines that attract T lymphocytes into the central nervous system. These T cells can then either amplify inflammation or, conversely, promote its resolution, depending on their type. For example, regulatory T lymphocytes secrete anti-inflammatory cytokines that modulate microglial activity and limit neuronal damage.

These discoveries highlight the therapeutic potential of microglia. Their ability to adapt and interact with many cells makes them a prime target for developing targeted treatments against neuroinflammatory diseases. By better understanding the signals that activate or inhibit them, researchers hope to modulate their activity to promote brain protection rather than its destruction. Approaches such as the use of antibodies targeting specific receptors or the modulation of intracellular signaling pathways are already under study.

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Reference Document

DOI: https://doi.org/10.1038/s41423-026-01438-3

Title: Microglia and neuroinflammation: function, heterogeneity, and crosstalk

Journal: Cellular & Molecular Immunology

Publisher: Springer Science and Business Media LLC

Authors: Shuai Zong; Xiaolin Cui; Shuang Wu; Zhiming Lu