Microglial cells, the resident immune cells of the central nervous system (CNS), play a crucial role in responding to neuroinflammatory stimuli. Scheiblich et al. demonstrated that microglia can form intercellular connections through tunneling nanotubes, facilitating the transfer and degradation of fibrillar alpha-synuclein (α-syn) from overloaded to naive microglia, highlighting a novel mechanism of cellular cooperation in protein clearance (ref: Scheiblich doi.org/10.1016/j.cell.2021.09.007/). In the context of traumatic brain injury (TBI), Holden et al. found that complement factor C1q is upregulated in the corticothalamic system, contributing to sleep spindle loss and epileptic spikes, indicating that neuroinflammation can have chronic effects on brain function post-injury (ref: Holden doi.org/10.1126/science.abj2685/). Additionally, Adams et al. explored the role of donor bone marrow-derived macrophages in chronic graft-versus-host disease (GVHD), revealing that MHC II expression drives neuroinflammation and behavioral changes, further emphasizing the impact of immune responses on CNS health (ref: Adams doi.org/10.1182/blood.2021011671/). Furthermore, Jie et al. identified that microglia promote autoimmune inflammation via the noncanonical NF-κB pathway, demonstrating the pivotal role of microglial activation in neuroinflammatory diseases like multiple sclerosis (ref: Jie doi.org/10.1126/sciadv.abh0609/). Overall, these studies underscore the multifaceted roles of microglia in neuroinflammation and their potential as therapeutic targets.

Microglia are increasingly recognized for their involvement in neurodegenerative diseases, particularly Alzheimer's disease (AD). Qiu et al. provided evidence that adult-onset deficiency of CNS myelin sulfatide leads to AD-like neuroinflammation and cognitive impairment, suggesting that lipid metabolism and immune responses are critical in AD pathology (ref: Qiu doi.org/10.1186/s13024-021-00488-7/). Huang et al. further supported this notion by showing that early AD pathology can be detected in cortical biopsies from patients with normal pressure hydrocephalus, where a shift from microglial homeostasis to a disease-associated phenotype correlates with increasing AD burden (ref: Huang doi.org/10.1038/s41467-021-25902-y/). Jiang et al. investigated the role of proteopathic tau in activating interleukin-1β via myeloid-cell-specific pathways, linking tau pathology to neuroinflammation in tauopathies (ref: Jiang doi.org/10.1016/j.celrep.2021.109720/). Additionally, Kim et al. demonstrated that transplantation of gut microbiota from an AD mouse model led to neuroinflammation and cognitive deficits in recipient mice, highlighting the influence of the gut-brain axis on microglial activation (ref: Kim doi.org/10.1016/j.bbi.2021.09.002/). Collectively, these findings illustrate the complex interplay between microglial activation and neurodegenerative processes, suggesting that targeting microglial responses may offer therapeutic avenues for AD.

Microglial plasticity is a critical aspect of their function in health and disease. Augusto-Oliveira et al. discussed how microglia, derived from fetal macrophages, undergo phenotypic changes influenced by their environment, allowing them to perform essential homeostatic functions in the nervous system (ref: Augusto-Oliveira doi.org/10.1111/brv.12797/). Washer et al. expanded on this by mapping microglial heterogeneity and identifying previously unknown cell states linked to disease, utilizing expression quantitative trait locus (eQTL) mapping techniques to reveal genetic influences on microglial behavior (ref: Washer doi.org/10.1016/j.tig.2021.09.004/). Furthermore, the role of interferon regulatory factor 8 (Irf8) in retinal microglial activation was highlighted by Zhang et al., who showed that Irf8 is essential for maintaining retinal homeostasis and preventing inflammation (ref: Zhang doi.org/10.1186/s12974-021-02230-y/). These studies collectively emphasize the dynamic nature of microglia and their ability to adapt to various stimuli, which can have profound implications for neuroinflammatory and neurodegenerative conditions.

Microglia are integral to synaptic function and maintenance, influencing neuronal connectivity and health. Dutta et al. explored the TLR2/MyD88/NF-κB signaling pathway, demonstrating that its selective inhibition reduces α-synuclein spreading and associated microglial inflammation, suggesting a potential therapeutic target for synucleinopathies (ref: Dutta doi.org/10.1038/s41467-021-25767-1/). Li et al. highlighted the role of phosphatidylserine exposure in synaptic pruning, where CDC50A is necessary for maintaining synapse integrity, indicating that microglial interactions with synapses are crucial for neuronal circuit refinement (ref: Li doi.org/10.15252/embj.2021107915/). Qin et al. provided insights into how PSD-93 influences synaptic activity in depression, linking microglial glutamate release to behavioral outcomes, thus connecting microglial function to mood disorders (ref: Qin doi.org/10.1007/s00401-021-02371-7/). These findings underscore the multifaceted roles of microglia in synaptic health and their potential impact on neuropsychiatric conditions.

Microglia are pivotal in orchestrating immune responses within the CNS, particularly in the context of neuroinflammatory diseases. Jie et al. demonstrated that microglia promote autoimmune inflammation through the noncanonical NF-κB pathway, highlighting their role in the progression of experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis (ref: Jie doi.org/10.1126/sciadv.abh0609/). Augusto-Oliveira et al. discussed the evolutionary conservation of microglial functions, emphasizing their role in maintaining homeostasis and responding to pathological stimuli (ref: Augusto-Oliveira doi.org/10.1111/brv.12797/). The study by Zhang et al. further elucidated the role of Irf8 in retinal microglial activation, showing that it is crucial for preventing inflammation and maintaining tissue integrity (ref: Zhang doi.org/10.1186/s12974-021-02230-y/). These studies collectively illustrate the essential functions of microglia in immune responses and their potential as therapeutic targets in neuroinflammatory conditions.

Emerging therapeutic strategies targeting microglia aim to mitigate neuroinflammation and promote neuroprotection. Adams et al. investigated the role of donor bone marrow-derived macrophages in chronic GVHD, revealing that MHC II expression drives neuroinflammation and behavioral changes, suggesting that modulating microglial responses could alleviate cognitive dysfunction in this context (ref: Adams doi.org/10.1182/blood.2021011671/). Qiu et al. highlighted that sulfatide deficiency in the CNS can lead to AD-like neuroinflammation, indicating that restoring lipid metabolism may be a viable therapeutic approach (ref: Qiu doi.org/10.1186/s13024-021-00488-7/). Dutta et al. demonstrated that targeting the TLR2/MyD88/NF-κB pathway can reduce α-synuclein spreading and associated inflammation, providing a potential strategy for treating synucleinopathies (ref: Dutta doi.org/10.1038/s41467-021-25767-1/). These findings underscore the potential of targeting microglial pathways to develop novel therapeutic interventions for neurodegenerative diseases.

Microglia play a critical role in the response to brain injury and subsequent repair processes. Holden et al. found that complement factor C1q is upregulated following mild traumatic brain injury (mTBI), contributing to sleep spindle loss and epileptic spikes, which underscores the long-term effects of brain injury on microglial activation and function (ref: Holden doi.org/10.1126/science.abj2685/). Adams et al. further explored the implications of chronic GVHD on neuroinflammation, revealing that behavioral deficits are associated with persistent microglial activation, suggesting that targeting these responses may improve outcomes in patients (ref: Adams doi.org/10.1182/blood.2021011671/). Campagno et al. examined the effects of increased intraocular pressure on microglial morphology and activation, indicating that environmental factors can significantly influence microglial responses to injury (ref: Campagno doi.org/10.1186/s12974-021-02251-7/). Together, these studies highlight the importance of microglia in mediating responses to brain injury and their potential role in therapeutic strategies for recovery.

Microglia are highly responsive to environmental factors, which can significantly influence their activation and function. Li et al. investigated the role of CDC50A in synapse maintenance, showing that its absence disrupts phosphatidylserine exposure, a critical signal for synaptic pruning, thereby affecting microglial interactions with synapses (ref: Li doi.org/10.15252/embj.2021107915/). Zhang et al. highlighted the importance of Irf8 in retinal microglial activation, demonstrating that it is essential for maintaining tissue homeostasis and preventing inflammation under pathological conditions (ref: Zhang doi.org/10.1186/s12974-021-02230-y/). Additionally, Beebe-Wang et al. introduced a unified AI framework to analyze gene expression and its relationship with Alzheimer's disease neuropathologies, emphasizing the role of environmental factors in shaping microglial responses (ref: Beebe-Wang doi.org/10.1038/s41467-021-25680-7/). These findings collectively illustrate how environmental cues can modulate microglial behavior, impacting their role in health and disease.