Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in neuroinflammation and neuronal health. Recent studies have highlighted the multifaceted functions of microglia, including their involvement in synaptic pruning and response to injury. For instance, Scott-Hewitt et al. demonstrated that microglial-derived C1q integrates into neuronal ribonucleoprotein complexes, impacting protein homeostasis in the aging brain, suggesting a critical role for microglia in maintaining synaptic integrity (ref: Scott-Hewitt doi.org/10.1016/j.cell.2024.05.058/). Chen et al. further elucidated the dynamics of astrocytic ATP release, termed Inflares, which are selectively released following brain injury and serve as internal representations of injury, indicating a complex interplay between astrocytes and microglia in injury response (ref: Chen doi.org/10.1038/s41593-024-01680-w/). Moreover, studies have shown that microglia contribute to maladaptive plasticity in autonomic circuitry after spinal cord injury, emphasizing their role in neuroplasticity and potential dysautonomia (ref: Brennan doi.org/10.1126/scitranslmed.adi3259/). Contradictory findings arise from the investigation of microglial activation and its effects on neuronal synchrony, where microglia were found to maintain neuronal network organization despite phenotypic transformations induced by ATP signaling (ref: Berki doi.org/10.1038/s41467-024-49773-1/). Overall, these studies underscore the dual role of microglia in both promoting and mitigating neuroinflammation, with implications for neurodegenerative diseases and brain injury recovery.

Microglia have been implicated in various neurodegenerative diseases, where their dysregulation contributes to disease progression. In Alzheimer's disease, for example, the expression of tau protein follows patterns of functional and structural brain organization, with microglial activation playing a significant role in this process (ref: Ottoy doi.org/10.1038/s41467-024-49300-2/). Additionally, Limone et al. utilized single-nucleus sequencing to reveal that genetic risk factors for amyotrophic lateral sclerosis (ALS) are enriched in extratelencephalic neurons, which are particularly vulnerable to degeneration, highlighting the importance of microglial interactions in neuronal health (ref: Limone doi.org/10.1038/s43587-024-00640-0/). The role of microglia in mediating inflammation and cognitive deficits post-COVID-19 was also explored by Vanderheiden et al., who found that vaccination reduced IL-1β levels in the CNS, suggesting a protective role of microglia in post-viral cognitive sequelae (ref: Vanderheiden doi.org/10.1038/s41590-024-01868-z/). Furthermore, Beliën et al. identified CHIT1 as a predictor of disability progression in multiple sclerosis, linking microglial activation to clinical outcomes (ref: Beliën doi.org/10.1038/s41467-024-49312-y/). These findings collectively illustrate the complex and often detrimental role of microglia in neurodegenerative diseases, emphasizing the need for targeted therapeutic strategies.

The activation of microglia has profound implications for behavioral outcomes, particularly in the context of stress and neuroinflammation. Zhang et al. investigated the role of augmented microglial endoplasmic reticulum-mitochondria contacts in mediating depression-like behavior induced by chronic social defeat stress, suggesting that microglial activation can directly influence mood and behavior (ref: Zhang doi.org/10.1038/s41467-024-49597-z/). Similarly, Li et al. demonstrated that conditional knockout of Pdcd4 in microglia mitigated neuroinflammation-associated depression, indicating that microglial regulation of inflammatory pathways is crucial for maintaining emotional health (ref: Li doi.org/10.1186/s12974-024-03142-3/). Furthermore, the study by Kang et al. revealed sex-dimorphic transcriptional changes in aging microglia, which may contribute to differential behavioral outcomes in males and females (ref: Kang doi.org/10.1186/s12974-024-03130-7/). The interplay between microglial activation and cognitive function was further highlighted by Bedolla et al., who found that TGF-β1 produced by microglia is essential for cognitive maintenance, linking microglial health to behavioral performance (ref: Bedolla doi.org/10.1038/s41467-024-49596-0/). These studies collectively underscore the critical role of microglia in shaping behavioral outcomes through their influence on neuroinflammation and synaptic function.

Recent advancements in therapeutic strategies targeting microglia have shown promise in modulating neuroinflammation and improving outcomes in various neurological conditions. Najem et al. explored the efficacy of the STING agonist 8803 in reprogramming the immune microenvironment in glioblastoma, resulting in increased survival rates in preclinical models (ref: Najem doi.org/10.1172/JCI175033/). This study highlights the potential of targeting microglial pathways to enhance anti-tumor immunity. Additionally, Arrieta et al. demonstrated that ultrasound-mediated delivery of doxorubicin to the brain not only improved drug concentration but also modulated immune responses, enhancing the efficacy of PD-1 blockade in gliomas (ref: Arrieta doi.org/10.1038/s41467-024-48326-w/). The role of microglia in mediating therapeutic effects was further emphasized by Wu et al., who investigated the expression of METTL3 in the context of traumatic brain injury, suggesting that microglial modulation could be a viable therapeutic approach (ref: Wu doi.org/10.1038/s41418-024-01329-y/). These findings collectively point to the importance of microglial targeting in developing effective therapies for neurodegenerative diseases and brain tumors.

Microglia are central to the immune responses within the CNS, acting as both sensors and effectors of neuroinflammation. Recent studies have highlighted their role in various pathological contexts, including neurodegenerative diseases and infections. For instance, the work by Arrieta et al. demonstrated that doxorubicin delivery via ultrasound enhances microglial activation and MHC expression, suggesting a critical role for microglia in orchestrating immune responses against tumors (ref: Arrieta doi.org/10.1038/s41467-024-48326-w/). Additionally, the study by Vanderheiden et al. revealed that vaccination against SARS-CoV-2 reduced IL-1β levels in the CNS, indicating that microglial activation can be modulated to alleviate cognitive deficits associated with viral infections (ref: Vanderheiden doi.org/10.1038/s41590-024-01868-z/). Furthermore, Cooze et al. utilized digital pathology to identify associations between inflammatory biomarkers and clinical outcomes in multiple sclerosis, underscoring the importance of microglial responses in disease progression (ref: Cooze doi.org/10.3390/cells13121020/). These findings collectively emphasize the dual role of microglia in both protective and pathological immune responses within the CNS.

The role of microglia in aging and development has garnered significant attention, particularly regarding their contributions to neurodevelopmental outcomes and age-related neurodegeneration. Kang et al. highlighted that aging microglia exhibit sex-dimorphic transcriptional and metabolic changes, with female microglia showing more pronounced aging-associated alterations than their male counterparts (ref: Kang doi.org/10.1186/s12974-024-03130-7/). This suggests that sex differences may influence microglial function and, consequently, brain health across the lifespan. Additionally, Batorsky et al. provided insights into the shared ontogeny of fetal brain microglia and Hofbauer cells, indicating that maternal diet-induced obesity can program microglial responses in offspring, potentially impacting neurodevelopment (ref: Batorsky doi.org/10.1016/j.celrep.2024.114326/). Furthermore, Scott-Hewitt et al. discussed the implications of microglial-derived C1q in synaptic pruning during aging, emphasizing the importance of microglial activity in maintaining neuronal health (ref: Scott-Hewitt doi.org/10.1016/j.cell.2024.05.058/). These studies collectively underscore the critical role of microglia in both aging and developmental processes, highlighting their potential as therapeutic targets for age-related neurodegenerative diseases.

Environmental factors significantly influence microglial function and their responses to injury and disease. Recent research has shown that maternal immune activation can lead to adverse neurodevelopmental outcomes in offspring, with Batorsky et al. demonstrating that maternal diet-induced obesity alters microglial programming in the fetal brain (ref: Batorsky doi.org/10.1016/j.celrep.2024.114326/). This highlights the importance of environmental influences on microglial development and function. Additionally, Chen et al. identified spatiotemporally selective ATP dynamics in astrocytes following brain injury, suggesting that microglial responses are intricately linked to the local microenvironment and injury context (ref: Chen doi.org/10.1038/s41593-024-01680-w/). Furthermore, the study by Vanderheiden et al. revealed that vaccination can modulate microglial activation and reduce neuroinflammation associated with COVID-19, indicating that environmental factors such as viral infections can significantly impact microglial behavior (ref: Vanderheiden doi.org/10.1038/s41590-024-01868-z/). Collectively, these findings underscore the dynamic interplay between microglia and their environment, emphasizing the need for further exploration of how environmental factors shape microglial function and contribute to neurological health.

Microglia play a crucial role in synaptic function and plasticity, influencing neuronal connectivity and overall brain health. Scott-Hewitt et al. highlighted the importance of microglial-derived C1q in synaptic pruning, demonstrating that this complement protein integrates into neuronal ribonucleoprotein complexes, thereby impacting protein homeostasis in the aging brain (ref: Scott-Hewitt doi.org/10.1016/j.cell.2024.05.058/). This suggests that microglia are not merely passive observers but active participants in maintaining synaptic integrity. Furthermore, Brennan et al. provided evidence that microglia promote maladaptive plasticity in autonomic circuitry following spinal cord injury, indicating their role in shaping synaptic responses to injury (ref: Brennan doi.org/10.1126/scitranslmed.adi3259/). Additionally, Berki et al. explored how microglia contribute to neuronal synchrony in acute brain slices, revealing that microglial phenotypes can significantly influence network organization and functioning (ref: Berki doi.org/10.1038/s41467-024-49773-1/). These studies collectively underscore the integral role of microglia in modulating synaptic function and highlight their potential as therapeutic targets for enhancing synaptic health in various neurological conditions.