Microglial cells play a crucial role in neuroinflammation, with various studies highlighting their functions in different pathological contexts. One study demonstrated that AIM2, an inflammasome sensor, negatively regulates the pathogenesis of experimental autoimmune encephalomyelitis (EAE) by inhibiting microglial activation and peripheral immune cell infiltration into the central nervous system (CNS), thus preventing neuroinflammation and demyelination (ref: Ma doi.org/10.1084/jem.20201796/). In contrast, another study found that microglial PGC-1α expression is upregulated following ischemic stroke, which helps protect against brain injury by suppressing neuroinflammation (ref: Han doi.org/10.1186/s13073-021-00863-5/). Furthermore, research on multiple sclerosis revealed that meningeal inflammation induces phenotypic changes in cortical microglia, which are associated with neurodegeneration, suggesting a complex interplay between microglial activation and disease progression (ref: van Olst doi.org/10.1007/s00401-021-02293-4/). These findings collectively underscore the dual role of microglia in both promoting and resolving neuroinflammation, depending on the context and stimuli present in the CNS environment. Additionally, the study of microglial responses to various inflammatory stimuli has revealed the potential for harnessing their properties for therapeutic purposes. For instance, exposure to IL-4 and IL-13 has been shown to elicit repair mechanisms in macrophages and microglia, enhancing their remyelinating properties (ref: Mishra doi.org/10.1523/JNEUROSCI.1948-20.2021/). However, excessive inflammation can be detrimental, as evidenced by research indicating that activated microglia contribute to ependymal cell death following exposure to microbial neuraminidase (ref: Fernández-Arjona doi.org/10.1186/s12987-021-00249-0/). This highlights the importance of understanding the balance between beneficial and harmful microglial activation in the context of neuroinflammatory diseases.

Microglia have been implicated in the progression of neurodegenerative diseases, particularly in Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). In AD, plaque-associated microglia have been shown to hyper-secrete extracellular vesicles that accelerate tau propagation, suggesting a paradoxical role where microglia contribute to disease progression despite their phagocytic activity (ref: Clayton doi.org/10.1186/s13024-021-00440-9/). Moreover, the characterization of disease-associated microglia (DAMs) in ALS has revealed a complex inflammatory state regulated by RIPK1, which is crucial for understanding microglial contributions to neurodegeneration (ref: Mifflin doi.org/10.1073/pnas.2025102118/). These findings indicate that while microglia are essential for clearing pathological proteins, their activation can also exacerbate neurodegenerative processes. In addition to AD and ALS, the role of microglia in major depressive disorder (MDD) has garnered attention, with studies linking structural brain abnormalities to specific transcriptional signatures in microglial cells (ref: Li doi.org/10.1038/s41467-021-21943-5/). The interplay between microglial activation and depressive symptoms highlights the potential for targeting neuroinflammatory pathways as therapeutic strategies. Furthermore, the activation of endogenous retroviruses during brain development has been implicated in inflammatory responses that may contribute to neurodevelopmental disorders, emphasizing the need for further research into the mechanisms by which microglia influence both neurodegenerative and psychiatric conditions (ref: Jönsson doi.org/10.15252/embj.2020106423/).

The response of microglia to brain injury is critical for recovery and repair mechanisms. Research has identified key cytokines, such as M-CSF, IL-6, and TGF-β, that promote the generation of a new subset of tissue repair macrophages, which are essential for traumatic brain injury (TBI) recovery (ref: Li doi.org/10.1126/sciadv.abb6260/). These cytokines were found to be elevated in patients with better TBI outcomes, suggesting their potential as therapeutic targets. Additionally, IL-4-driven microglia have been shown to modulate stress resilience through BDNF-dependent neurogenesis, indicating that specific microglial populations play a role in neuroplasticity and recovery from stress (ref: Zhang doi.org/10.1126/sciadv.abb9888/). Moreover, the use of bone marrow mesenchymal stem cell-derived exosomes has been explored for their neuroprotective effects, demonstrating the ability to modulate microglial polarization and reduce neuroinflammation and pyroptosis following cerebral ischemia-reperfusion injury (ref: Liu doi.org/10.1016/j.expneurol.2021.113700/). This highlights the potential of leveraging microglial responses for therapeutic interventions in neuroinflammatory conditions. However, the detrimental effects of activated microglia were also observed, as they contributed to ependymal cell death in response to microbial neuraminidase, underscoring the complexity of microglial roles in injury contexts (ref: Fernández-Arjona doi.org/10.1186/s12987-021-00249-0/). Understanding these dual roles is essential for developing strategies that harness the beneficial aspects of microglial activation while mitigating their harmful effects.

Microglia interact intricately with the immune system, influencing both local and systemic immune responses. A study investigating the role of AIM2 in EAE revealed that its deficiency leads to enhanced microglial activation and increased infiltration of peripheral immune cells into the CNS, promoting neuroinflammation and demyelination (ref: Ma doi.org/10.1084/jem.20201796/). This highlights the importance of microglial regulation in autoimmune conditions and their potential as therapeutic targets. Furthermore, meningeal inflammation in multiple sclerosis was shown to induce phenotypic changes in cortical microglia, which were associated with neurodegeneration, suggesting that microglia are not only responders but also active participants in disease progression (ref: van Olst doi.org/10.1007/s00401-021-02293-4/). Additionally, the generation of macrophages and microglia with prominent remyelinating properties through specific cytokine exposure indicates that microglia can adopt beneficial roles in the context of neuroinflammation (ref: Mishra doi.org/10.1523/JNEUROSCI.1948-20.2021/). This adaptability underscores the potential for manipulating microglial responses to enhance repair mechanisms in neurodegenerative diseases. The correlation between structural differences in the brain and transcriptional signatures in MDD further emphasizes the role of microglia in psychiatric disorders, suggesting that immune interactions may influence both neurodevelopmental and neuropsychiatric outcomes (ref: Li doi.org/10.1038/s41467-021-21943-5/).

Microglial activation plays a pivotal role in neurodevelopment, influencing brain maturation and function. Recent studies have shown that maternal immune activation can impact microglial function in the developing brain, potentially leading to neurodevelopmental disorders. For instance, research utilizing umbilical cord blood-derived microglia-like cells has aimed to model the effects of COVID-19 exposure on fetal brain development, highlighting the importance of understanding how maternal infections can prime microglial responses (ref: Sheridan doi.org/10.1038/s41398-021-01287-w/). This underscores the need for further investigation into the mechanisms by which microglia contribute to neurodevelopmental outcomes. Moreover, the activation of endogenous retroviruses during brain development has been linked to inflammatory responses, suggesting that microglial activation may be a response to such triggers (ref: Jönsson doi.org/10.15252/embj.2020106423/). Additionally, the study of ischemic sexual dimorphism has revealed that microglial responses can be influenced by epigenetic modifications, impacting inflammatory cytokine production and potentially contributing to sex differences in neurodevelopmental outcomes (ref: Qi doi.org/10.1186/s12974-021-02120-3/). These findings collectively highlight the critical role of microglia in shaping neurodevelopment and the potential long-term consequences of altered microglial activation during critical periods of brain maturation.

The involvement of microglia in psychiatric disorders has gained increasing attention, particularly in the context of major depressive disorder (MDD). Studies have shown that structural abnormalities in the brains of individuals with MDD correlate with specific transcriptional signatures in microglial cells, suggesting that microglial activation may play a role in the pathophysiology of depression (ref: Li doi.org/10.1038/s41467-021-21943-5/). This connection between microglial function and mood disorders highlights the potential for targeting neuroinflammatory pathways as therapeutic strategies for MDD. Additionally, the role of AIM2 in regulating microglial inflammation has been implicated in the context of autoimmune diseases, such as EAE, which shares overlapping features with psychiatric disorders (ref: Ma doi.org/10.1084/jem.20201796/). Furthermore, the generation of macrophages and microglia with remyelinating properties through cytokine exposure suggests that modulating microglial responses could have therapeutic implications for both neurodegenerative and psychiatric conditions (ref: Mishra doi.org/10.1523/JNEUROSCI.1948-20.2021/). The exploration of microglial mechanisms in psychiatric disorders is essential for understanding the complex interplay between immune responses and mental health.

Aging is associated with significant changes in microglial function, which can impact neuroinflammatory processes and contribute to age-related neurodegenerative diseases. Research has shown that the activation of endogenous retroviruses during brain development can trigger inflammatory responses, suggesting that dysregulation of microglial activation may have long-term effects on brain health (ref: Jönsson doi.org/10.15252/embj.2020106423/). This highlights the importance of understanding how aging influences microglial responses and their role in maintaining homeostasis in the aging brain. Moreover, studies have indicated that AIM2 plays a critical role in regulating microglial inflammation, which is particularly relevant in the context of age-related diseases such as Alzheimer's (ref: Ma doi.org/10.1084/jem.20201796/). The exploration of engineered microglia as potential therapeutic vectors for drug delivery in glioma treatment further emphasizes the adaptability of microglial functions in response to aging and disease (ref: Du doi.org/10.1002/adhm.202002200/). Understanding the mechanisms underlying microglial activation and their implications for aging is crucial for developing interventions aimed at promoting brain health in older adults.

Microglia play a significant role in the tumor microenvironment, particularly in glioblastoma, where they can influence tumor progression and response to therapy. Recent studies utilizing single-cell RNA sequencing have revealed the dynamics of myeloid cells in glioblastoma, highlighting the competition and specialization among macrophages and microglia during disease progression (ref: Pombo Antunes doi.org/10.1038/s41593-020-00789-y/). This research underscores the complexity of microglial interactions within the tumor microenvironment and their potential as therapeutic targets. Additionally, the ability of engineered microglia to enhance the delivery of therapeutic agents against glioma through extracellular vesicles and tunneling nanotubes presents new opportunities for cancer treatment (ref: Du doi.org/10.1002/adhm.202002200/). Furthermore, the modulation of microglial responses through neuroinflammatory pathways may also have implications for the treatment of other cancers, suggesting a broader role for microglia in cancer biology. Understanding the mechanisms by which microglia contribute to tumor progression and therapy resistance is essential for developing effective cancer therapies.