Radiation exposure profoundly influences microglia activity in the brain, triggering a complex cascade of cellular and molecular events that alter their behavior and function. Microglia, the resident immune cells of the central nervous system (CNS), serve as the primary responders to brain injury and maintain homeostasis by constantly surveying their environment. When exposed to ionizing radiation, microglia rapidly detect damage signals and shift from a resting, homeostatic state to an activated, reactive state, which can have both protective and detrimental effects on neural tissue.
At the core of radiation’s impact on microglia is the generation of reactive oxygen species (ROS). Ionizing radiation induces oxidative stress by producing ROS, which damage cellular components including DNA, proteins, and lipids. This oxidative stress leads to mitochondrial dysfunction within microglia, causing the release of mitochondrial DNA into the cytosol. This mitochondrial DNA acts as a danger signal, activating innate immune pathways such as the cGAS-STING pathway. Activation of this pathway drives a persistent inflammatory response mediated by microglia, characterized by the release of pro-inflammatory cytokines and chemokines. This chronic neuroinflammation can exacerbate neuronal damage and contribute to cognitive deficits observed after cranial irradiation.
Microglia also engage in cross-talk with other CNS cells, including neurons, astrocytes, and oligodendrocytes, to coordinate the brain’s response to radiation-induced injury. They modulate the blood-brain barrier (BBB), influencing its permeability and controlling the infiltration of peripheral immune cells. Radiation-induced microglial activation can disrupt the neurovascular unit, severing the support between neural progenitors and their microvasculature, which impairs neurogenesis and brain repair mechanisms. This disruption contributes to long-term cognitive impairments such as memory loss, reduced attention, and executive dysfunction.
On a molecular level, radiation activates DNA damage response pathways in microglia, including NF-κB, CREB, and AP1 transcription factors, which upregulate inflammatory mediators like interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX2), and monocyte chemoattractant protein-1 (MCP1). These factors amplify the inflammatory milieu, recruiting additional immune cells and perpetuating microglial activation. Unlike peripheral tissues, the CNS relies heavily on microglia to gate inflammation, partly through the expression of tight junction proteins such as claudin-5, which restricts peripheral immune cell infiltration more stringently than in other organs.
Microglia exhibit remarkable plasticity in response to radiation. Initially, they may adopt a phenotype aimed at clearing damaged cells and debris through phagocytosis, expressing genes involved in lipid processing and antigen presentation. Over time, their transcriptional profile can shift toward chronic inflammatory states, producing interferons and other molecules that sustain neuroinflammation. This dynamic phenotypic change is crucial for orchestrating repair but can also lead to neurotoxicity if the inflammatory response becomes excessive or unresolved.
Experimental models have shown that manipulating microglial activity can influence outcomes after radiation exposure. For example, reducing microglial proliferation or selectively inhibiting inflammatory pathways like STING can mitigate radiation-induced neurotoxicity and improve cognitive function. Conversely, loss of certain microglial signaling molecules, such as RhoA, impairs their ability to adapt metabolically and functionally to injury, hindering brain repair processes.
In summary, radiation exposure activates microglia through oxidative stress and mitochondrial damage, triggering innate immune pathways that lead to sustained neuroinflammation. This microglial activation disrupts neurovascular integrity, impairs neurogenesis, and contributes to cognitive deficits. The balance between protective and harmful microglial responses is delicate, and ongoing research aims to develop targeted therapies that modulate microglial activity to protect the brain from radiation-induce