Microglia play a crucial role in regulating neuroinflammation and brain activity, as evidenced by Klawonn et al. who demonstrated that microglial activation in the striatum initiates an IL-6-mediated autocrine loop, leading to the release of prostaglandins that induce negative affective states through the stimulation of medium spiny neurons (ref: Matteoli doi.org/10.1016/j.immuni.2021.01.010/). In the context of multiple sclerosis, Dong et al. identified oxidized phosphatidylcholines (OxPCs) in MS lesions as potent drivers of neurodegeneration, which microglia can neutralize, highlighting their protective role against neurodegenerative processes (ref: Dong doi.org/10.1038/s41593-021-00801-z/). Furthermore, Guttikonda et al. developed a tri-culture system using human pluripotent stem cell-derived microglia to model neuroinflammation in Alzheimer's disease, revealing the complex interactions between microglia, astrocytes, and neurons (ref: Guttikonda doi.org/10.1038/s41593-020-00796-z/). This model allows for a deeper understanding of the neuroinflammatory axis and its implications in neurodegenerative diseases. Additionally, Bekhbat et al. explored how chronic adolescent stress sensitizes the adult neuroimmune transcriptome, leading to sex-specific microglial and behavioral phenotypes, indicating the long-term effects of early-life stress on microglial function (ref: Bekhbat doi.org/10.1038/s41386-021-00970-2/). Zheng et al. further contributed to this theme by showing that ceria nanoparticles can ameliorate white matter injury after intracerebral hemorrhage through microglial and astrocytic involvement in remyelination, suggesting potential therapeutic avenues for neuroinflammatory conditions (ref: Zheng doi.org/10.1186/s12974-021-02101-6/).

Research on microglia in neurodegenerative diseases has highlighted their dual roles in both promoting and mitigating pathology. Schwartzentruber et al. conducted a genome-wide meta-analysis that identified 37 risk loci for Alzheimer's disease, including new associations that may implicate microglial function in disease mechanisms (ref: Schwartzentruber doi.org/10.1038/s41588-020-00776-w/). Gerrits et al. characterized distinct microglial profiles associated with amyloid-β and tau pathology in Alzheimer's disease, revealing that AD1-microglia correlate with amyloid-β load while AD2-microglia correlate with phospho-tau load, suggesting that microglial responses are tailored to specific pathological features (ref: Gerrits doi.org/10.1007/s00401-021-02263-w/). Marzan et al. demonstrated that activated microglia drive demyelination in multiple sclerosis via CSF1R signaling, indicating that microglial activation is a critical factor in the progression of neurodegenerative diseases (ref: Marzan doi.org/10.1002/glia.23980/). Kenkhuis et al. found that iron accumulation in microglia exacerbates Alzheimer's disease progression, linking microglial activation to iron dysregulation in the brain (ref: Kenkhuis doi.org/10.1186/s40478-021-01126-5/). Wißfeld et al. explored the role of CD33 in microglial activation, showing that deletion of this gene results in an inflammatory phenotype, further implicating microglial dysfunction in Alzheimer's disease (ref: Wißfeld doi.org/10.1002/glia.23968/).

Microglial response to injury is a critical area of research, particularly in understanding their role in repair mechanisms following CNS damage. Guttikonda et al. developed a tri-culture system to model neuroinflammation in Alzheimer's disease, allowing for the dissection of microglial interactions with astrocytes and neurons, which is essential for understanding their reparative functions (ref: Guttikonda doi.org/10.1038/s41593-020-00796-z/). Wahane et al. utilized single-cell RNA sequencing to reveal diverse transcriptional responses of myeloid and glial cells in spinal cord injury, highlighting the complexity of microglial activation states and their potential roles in neural repair (ref: Wahane doi.org/10.1126/sciadv.abd8811/). Ochocka et al. examined glioma-associated macrophages, uncovering functional heterogeneity that may influence tumor progression and repair mechanisms in glioblastoma (ref: Ochocka doi.org/10.1038/s41467-021-21407-w/). Additionally, Zhang et al. investigated the effects of berberine on spinal microglial activation in models of visceral hypersensitivity, suggesting that targeting microglial activation may provide therapeutic benefits in various conditions (ref: Zhang doi.org/10.1038/s41401-020-00601-4/).

The activation of microglia and their immune responses are pivotal in the context of neuroinflammation and CNS pathology. Klawonn et al. demonstrated that microglial activation in the striatum can lead to an IL-6-mediated autocrine loop, which is associated with negative affective states, thereby linking microglial activity to mood disorders (ref: Matteoli doi.org/10.1016/j.immuni.2021.01.010/). Kveštak et al. explored the role of NK/ILC1 cells in mediating neuroinflammation following congenital cytomegalovirus infection, revealing that microglia-derived chemokines play a significant role in recruiting immune cells to the CNS (ref: Kveštak doi.org/10.1084/jem.20201503/). Hayes et al. provided insights into the role of ASC-dependent inflammasomes in herpes simplex encephalitis, suggesting that microglial activation contributes to pathogenic inflammation and may serve as a target for therapeutic intervention (ref: Hayes doi.org/10.1371/journal.ppat.1009285/). Furthermore, Zheng et al. reported that ceria nanoparticles can modulate microglial activation and promote remyelination after intracerebral hemorrhage, indicating potential therapeutic strategies for enhancing microglial function in injury contexts (ref: Zheng doi.org/10.1186/s12974-021-02101-6/).

Microglial diversity and their responses to aging are critical for understanding neurodegenerative processes. Safaiyan et al. identified white matter-associated microglia (WAMs) that exhibit a unique gene signature related to phagocytic activity and lipid metabolism, emphasizing the role of aging in shaping microglial diversity (ref: Safaiyan doi.org/10.1016/j.neuron.2021.01.027/). Yang et al. demonstrated that natural genetic variation significantly influences microglial heterogeneity in mouse models of Alzheimer's disease, suggesting that genetic factors may dictate microglial responses to neurodegeneration (ref: Yang doi.org/10.1016/j.celrep.2021.108739/). Guttikonda et al. further contributed to this theme by developing a tri-culture system to study microglial interactions in the context of aging and neuroinflammation, providing insights into how these cells adapt to pathological changes (ref: Guttikonda doi.org/10.1038/s41593-020-00796-z/). Additionally, Zhang et al. explored the effects of berberine on microglial activation in models of visceral hypersensitivity, highlighting the potential for therapeutic interventions targeting microglial function in aging-related disorders (ref: Zhang doi.org/10.1038/s41401-020-00601-4/).

Identifying therapeutic targets for modulating microglial activity is essential for developing treatments for neurodegenerative diseases. Guttikonda et al. created a tri-culture system to model neuroinflammation in Alzheimer's disease, which may serve as a platform for testing potential therapies aimed at modulating microglial responses (ref: Guttikonda doi.org/10.1038/s41593-020-00796-z/). Wahane et al. highlighted the role of HDAC3 in shaping the transcriptional responses of myeloid and glial cells after spinal cord injury, suggesting that targeting epigenetic regulators could influence microglial activation and repair mechanisms (ref: Wahane doi.org/10.1126/sciadv.abd8811/). Browne et al. investigated neuropsychiatric lupus in a mouse model, revealing behavioral phenotypes that could be linked to microglial activation, thus presenting a potential target for therapeutic intervention (ref: Browne doi.org/10.1016/j.bbi.2021.02.010/). Hayes et al. also emphasized the potential of targeting inflammasome activation in microglia as a therapeutic strategy for herpes simplex encephalitis, providing a new avenue for combating harmful inflammation (ref: Hayes doi.org/10.1371/journal.ppat.1009285/). Zheng et al. reported that ceria nanoparticles can ameliorate white matter injury by modulating microglial activation, indicating their potential as therapeutic agents in neuroinflammatory conditions (ref: Zheng doi.org/10.1186/s12974-021-02101-6/).

Microglia are integral to both CNS development and the progression of various diseases. Klawonn et al. illustrated that microglial activation in the striatum can influence emotional states, linking their function to neurodevelopmental processes (ref: Matteoli doi.org/10.1016/j.immuni.2021.01.010/). Guttikonda et al. developed a tri-culture system to study microglial interactions with neurons and astrocytes, providing insights into their role in neuroinflammation during Alzheimer's disease (ref: Guttikonda doi.org/10.1038/s41593-020-00796-z/). Kälin et al. characterized tumor-associated myeloid-like cells in glioblastoma, revealing their role in neoplastic angiogenesis and progression, which underscores the importance of microglial and myeloid interactions in tumor biology (ref: Kälin doi.org/10.1016/j.cels.2021.01.002/). Hayes et al. demonstrated that inflammasome activation in microglia contributes to immunopathology in herpes simplex encephalitis, suggesting that microglial responses are critical in the context of viral infections (ref: Hayes doi.org/10.1371/journal.ppat.1009285/). Marzan et al. further explored the role of activated microglia in demyelination, providing evidence for their involvement in multiple sclerosis pathology (ref: Marzan doi.org/10.1002/glia.23980/).