Microglial activation plays a crucial role in neuroinflammation, particularly in conditions such as cerebral small vessel disease (SVD). Walsh et al. identified significant hotspots of increased microglial activation and blood-brain barrier (BBB) permeability in sporadic SVD, with a notable increase in both 11C-PK11195 binding and BBB permeability in normal appearing white matter (P = 0.003 and P = 0.007, respectively). This study highlights the potential for microglial activation to contribute to vascular dysfunction in neurodegenerative diseases (ref: Walsh doi.org/10.1093/brain/). Eyo et al. further explored microglial dynamics in the context of severe seizures, demonstrating that microglia form process pouches that target injured dendrites, aiding in their structural resolution. This suggests a protective role of microglia in the aftermath of neuronal injury (ref: Eyo doi.org/10.1016/j.celrep.2021.109080/). In another study, Yang et al. investigated the regulatory roles of miR-155 and miR-146a in neuroinflammatory responses during meningitic Escherichia coli infection, revealing that their suppression exacerbated inflammation and reduced survival in a mouse model (ref: Yang doi.org/10.1186/s12974-021-02165-4/). These findings collectively underscore the complex interplay between microglial activation and neuroinflammatory processes across various neurological conditions, including the differential responses elicited by TLR activation as shown by Schilling et al. (ref: Schilling doi.org/10.1016/j.bbi.2021.05.013/).

Microglia are increasingly recognized for their pivotal role in neurodegenerative diseases, particularly Alzheimer's disease (AD). Ayalon et al. demonstrated that the anti-tau monoclonal antibody semorinemab effectively reduces tau pathology in transgenic mouse models and engages tau in human patients, indicating a potential therapeutic avenue for AD (ref: Ayalon doi.org/10.1126/scitranslmed.abb2639/). In a related study, Vautheny et al. found that TREM2 deficiency in the THY-Tau22 mouse model exacerbates tauopathy at later disease stages, highlighting the importance of microglial signaling in disease progression (ref: Vautheny doi.org/10.1016/j.nbd.2021.105398/). Furthermore, the work by Alvarez-Vergara et al. revealed that non-productive angiogenesis around amyloid plaques leads to vascular disassembly, with microglial phagocytosis contributing to this process (ref: Alvarez-Vergara doi.org/10.1038/s41467-021-23337-z/). These studies collectively emphasize the dual role of microglia in both promoting and resolving neurodegenerative processes, as well as the potential for targeting microglial pathways for therapeutic benefit.

The neuroprotective roles of microglia are becoming increasingly evident, particularly in the context of neuroinflammation and injury. Heiss et al. demonstrated that gut microbiota influences hypothalamic inflammation and leptin sensitivity, suggesting that microglial activity may be modulated by systemic factors such as diet (ref: Heiss doi.org/10.1016/j.celrep.2021.109163/). In a study focusing on Parkinson's disease, Zhang et al. utilized a 'Trojan horse' delivery system to enhance the neuroprotective effects of 4,4'-dimethoxychalcone, illustrating innovative strategies to target microglial pathways for neuroprotection (ref: Zhang doi.org/10.1002/advs.202004555/). Additionally, Tian et al. explored the use of neural progenitor cell-derived extracellular vesicles for anti-inflammatory effects post-cerebral ischemia, further highlighting the therapeutic potential of modulating microglial responses in injury contexts (ref: Tian doi.org/10.7150/thno.56367/). These findings underscore the importance of microglial function in neuroprotection and recovery following neurological insults.

Microglia are critical mediators of pain mechanisms, particularly in neuropathic pain states. Navia-Pelaez et al. identified a cholesterol-driven mechanism in spinal microglia that regulates TLR4 signaling, which is pivotal in the development of neuropathic pain (ref: Navia-Pelaez doi.org/10.1084/jem.20202059/). This study suggests that targeting cholesterol metabolism in microglia could be a novel approach to alleviate pain. Furthermore, König et al. investigated the interactions between IL-1β, TNF, and IL-6 in spinal cord injury, revealing complex signaling pathways that contribute to mechanical hyperexcitability (ref: König doi.org/10.1111/jnc.15438/). In a different context, Wang et al. demonstrated that microglia-specific knockdown of Bmal1 enhances memory and protects against high-fat diet-induced obesity, indicating a link between microglial function and metabolic pain mechanisms (ref: Wang doi.org/10.1038/s41380-021-01169-z/). These studies collectively highlight the multifaceted roles of microglia in pain processing and the potential for targeting microglial pathways in pain management.

Microglia play a significant role in the recovery process following stroke, as evidenced by Shi et al., who found that Treg cell-derived osteopontin promotes microglia-mediated white matter repair after ischemic stroke (ref: Shi doi.org/10.1016/j.immuni.2021.04.022/). This study underscores the importance of microglial activation in facilitating tissue repair and regeneration post-stroke. Additionally, Xu et al. demonstrated that annexin A1 modulates microglial polarization, providing a protective effect against cerebral ischemia-reperfusion injury through the AMPK-mTOR signaling pathway (ref: Xu doi.org/10.1186/s12974-021-02174-3/). In contrast, Feng et al. highlighted the detrimental effects of iron overload in the motor cortex following spinal cord injury, where activated microglia contribute to neuronal ferroptosis, ultimately hindering recovery (ref: Feng doi.org/10.1016/j.redox.2021.101984/). These findings illustrate the dual roles of microglia in both promoting recovery and contributing to injury, emphasizing the need for targeted therapeutic strategies in stroke management.

The signaling pathways involving microglia are crucial for understanding their roles in health and disease. Jin et al. introduced scGRNom, a computational pipeline for predicting cell-type disease genes and regulatory networks, which can enhance our understanding of microglial signaling in diseases like schizophrenia and Alzheimer's (ref: Jin doi.org/10.1186/s13073-021-00908-9/). Miller-Rhodes et al. explored how the cell culture environment affects the transcription factor MafB in BV-2 microglia, revealing that lipid availability influences microglial behavior (ref: Miller-Rhodes doi.org/10.1016/j.cmet.2018.12.004/). Furthermore, Bocharova et al. demonstrated that Alzheimer's disease-associated β-amyloid does not protect against HSV-1 infection, implicating microglial phagocytic activity in the response to viral infections (ref: Bocharova doi.org/10.1016/j.jbc.2021.100845/). These studies collectively highlight the importance of cellular signaling in modulating microglial functions and responses to various stimuli.

Microglia are integral to the immune response in the central nervous system, as evidenced by several studies. Sloley et al. demonstrated that repeated head impacts lead to chronic cognitive impairments, with synaptic adaptations being a target of microglial response to trauma (ref: Sloley doi.org/10.1038/s41467-021-22744-6/). Eyo et al. provided insights into how microglia respond to severe seizures, forming process pouches that aid in the structural resolution of injured dendrites, indicating a protective role in the context of neuronal excitability (ref: Eyo doi.org/10.1016/j.celrep.2021.109080/). Additionally, Madhu et al. investigated the effects of melatonin on cognitive and mood functions in a chronic Gulf War Illness model, highlighting its potential to modulate neuroinflammation and improve outcomes (ref: Madhu doi.org/10.1016/j.redox.2021.101973/). Murdock et al. examined the role of NK cells in amyotrophic lateral sclerosis, revealing sex- and age-dependent effects on neuroinflammation, further emphasizing the complexity of immune interactions involving microglia (ref: Murdock doi.org/10.1172/jci.insight.147129/). These findings underscore the multifaceted roles of microglia in immune responses and their implications for neurodegenerative diseases.

Microglia are essential for development and repair processes in the central nervous system. Cavone et al. identified a unique macrophage subpopulation that directly signals to progenitor cells to promote neurogenesis in the zebrafish spinal cord, highlighting the regenerative potential of immune cells (ref: Cavone doi.org/10.1016/j.devcel.2021.04.031/). In the context of aging, Zhang et al. provided a comprehensive transcriptomic landscape of primate hippocampal aging, revealing significant phenotypic changes that may impact neurogenesis and repair mechanisms (ref: Zhang doi.org/10.1007/s13238-021-00852-9/). Eyo et al. also contributed to this theme by demonstrating how microglial dynamics following severe seizures can facilitate the resolution of dendritic injuries, suggesting a role in neuronal repair (ref: Eyo doi.org/10.1016/j.celrep.2021.109080/). These studies collectively emphasize the critical roles of microglia in both developmental processes and the repair of neural tissues following injury.