Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in maintaining homeostasis and responding to injury. Recent studies have highlighted their involvement in various neuroinflammatory processes and neurodegenerative diseases. For instance, research by Lin et al. demonstrates the potential of directed evolution of adeno-associated viruses to enhance gene delivery specifically to microglia, which could facilitate the study of microglial biology and associated disease mechanisms (ref: Lin doi.org/10.1038/s41592-022-01547-7/). Bi et al. further elucidate the regulatory role of microglia in neuronal excitability, showing that microglia-derived PDGF-B promotes potassium currents in pre-sympathetic neurons, thereby preventing overactivation and limiting hypertension (ref: Bi doi.org/10.1016/j.immuni.2022.06.018/). Additionally, the study by Gerrits et al. employs single-nucleus RNA sequencing to uncover neurovascular dysfunction in frontotemporal dementia, linking microglial activity to the disease pathology (ref: Gerrits doi.org/10.1038/s41593-022-01124-3/). These findings collectively underscore the multifaceted roles of microglia in both health and disease, emphasizing their importance in neuroinflammation and neuronal regulation. Moreover, the impact of microglial dysfunction in neurodegenerative conditions is further explored in studies focusing on Down syndrome and Alzheimer's disease. Jin et al. reveal that type-I interferon signaling drives microglial dysfunction and senescence in human iPSC models, suggesting that targeting this pathway could ameliorate microglial phenotypes associated with these conditions (ref: Jin doi.org/10.1016/j.stem.2022.06.007/). Kiral et al. corroborate these findings, showing that inhibiting interferon signaling rescues developmental and tau-associated phenotypes in Down syndrome microglia (ref: Kiral doi.org/10.1016/j.stem.2022.06.008/). Furthermore, the pathogenic role of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus highlights the intricate relationship between stress, microglial activation, and neuropsychiatric manifestations (ref: Abe doi.org/10.1136/ard-2022-222566/). Together, these studies illustrate the critical involvement of microglia in neuroinflammatory responses and their potential as therapeutic targets in various CNS disorders.

The role of microglia in neurodegenerative diseases has garnered significant attention, particularly in the context of Alzheimer's disease and frontotemporal dementia. Research by Gerrits et al. employs single-nucleus RNA sequencing to investigate neurovascular dysfunction in GRN-associated frontotemporal dementia, revealing insights into the cellular dynamics of microglia, astrocytes, and the neurovasculature (ref: Gerrits doi.org/10.1038/s41593-022-01124-3/). This study highlights the complex interplay between microglial activation and neurodegenerative processes, suggesting that alterations in microglial function contribute to disease pathology. Jin et al. further explore the implications of type-I interferon signaling in microglial dysfunction within human iPSC models of Down syndrome and Alzheimer's disease, demonstrating that this signaling pathway exacerbates microglial senescence and dysfunction (ref: Jin doi.org/10.1016/j.stem.2022.06.007/). Kiral et al. support these findings by showing that inhibiting this signaling pathway can rescue microglial phenotypes, indicating a potential therapeutic avenue for ameliorating neurodegenerative conditions (ref: Kiral doi.org/10.1016/j.stem.2022.06.008/). In addition, Casaletto et al. investigate sex-specific effects of microglial activation on Alzheimer's disease proteinopathy, revealing that microglial activation mediates a significant portion of the relationship between amyloid-β and tau in females, while in males, the direct effect of microglial activation on tau is more pronounced (ref: Casaletto doi.org/10.1093/brain/). This finding underscores the necessity of considering sex differences in microglial responses when studying neurodegenerative diseases. Furthermore, Van Schoor et al. highlight the role of pyroptosis in ALS, linking increased activation of this inflammatory cell death pathway in microglia to neuronal loss in the motor cortex (ref: Van Schoor doi.org/10.1007/s00401-022-02466-9/). Collectively, these studies emphasize the critical role of microglia in the pathogenesis of neurodegenerative diseases, revealing both their protective and detrimental functions, and highlighting the need for targeted therapeutic strategies.

Microglial responses to injury are crucial for CNS repair and regeneration. Brennan et al. investigate the role of microglia in spinal cord injury (SCI), demonstrating that these cells coordinate cellular interactions during the repair process. By pharmacologically depleting microglia and employing various techniques, including RNA sequencing, the study reveals the specific cellular and molecular responses orchestrated by microglia in the context of SCI (ref: Brennan doi.org/10.1038/s41467-022-31797-0/). This research highlights the complexity of microglial activation and their essential role in mediating neuroinflammatory responses following injury. In the context of neurodegenerative diseases, Van Schoor et al. also explore the activation of pyroptosis in microglia during ALS, linking this inflammatory cell death pathway to neuronal loss in the motor cortex (ref: Van Schoor doi.org/10.1007/s00401-022-02466-9/). This suggests that microglial responses to injury can have both protective and harmful effects, depending on the context and timing of their activation. Additionally, Li et al. investigate the role of microglial mitophagy in regulating neuroinflammation during herpes simplex encephalitis, revealing that gut microbial metabolites can influence microglial function and mitigate disease progression (ref: Li doi.org/10.1080/15548627.2022.2102309/). These findings collectively underscore the dual nature of microglial responses to injury, where their activation can either promote repair or contribute to neurodegeneration, emphasizing the need for a nuanced understanding of microglial biology in injury contexts.

Microglia play a significant role in immune modulation within the CNS, influencing both neuroinflammatory responses and neuropsychiatric outcomes. Abe et al. investigate the pathogenic effects of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus, demonstrating that stress exacerbates neuropsychiatric symptoms through microglial activation (ref: Abe doi.org/10.1136/ard-2022-222566/). This study highlights the intricate relationship between stress, immune modulation, and neuropsychiatric disorders, suggesting that targeting microglial pathways may offer therapeutic benefits. Furthermore, Jiang et al. elucidate the role of NFAT1 in orchestrating microglial transcription and proliferation, linking this transcription factor to nerve injury-induced neuropathic pain (ref: Jiang doi.org/10.1002/advs.202201300/). The findings indicate that NFAT1 regulates the expression of various microglia-related genes, underscoring its importance in microglial activation and immune responses. Additionally, Piec et al. explore the therapeutic potential of muramyl dipeptide in delaying Alzheimer's disease physiopathology via NOD2 receptors, suggesting that modulation of innate immune cells can effectively alter disease progression (ref: Piec doi.org/10.3390/cells11142241/). Collectively, these studies emphasize the critical role of microglia in immune modulation within the CNS, highlighting their potential as therapeutic targets for various neuroinflammatory and neurodegenerative conditions.

Microglial activation during neurodevelopment is crucial for proper brain formation and function. Jin et al. investigate the impact of type-I interferon signaling on microglial dysfunction and senescence in human iPSC models of Down syndrome and Alzheimer's disease, revealing that this signaling pathway exacerbates microglial phenotypes during brain development (ref: Jin doi.org/10.1016/j.stem.2022.06.007/). This study highlights the importance of understanding how genetic factors can influence microglial behavior during critical developmental windows. Kiral et al. further support these findings by demonstrating that human Down syndrome microglia exhibit enhanced synaptic engulfment and accelerated tau-induced cellular senescence, suggesting that microglial activation can have profound effects on synaptic development and maintenance (ref: Kiral doi.org/10.1016/j.stem.2022.06.008/). Additionally, the study by Van Schoor et al. on ALS emphasizes the role of microglial pyroptosis in neuronal loss, indicating that neuroinflammation can disrupt normal neurodevelopmental processes (ref: Van Schoor doi.org/10.1007/s00401-022-02466-9/). Together, these studies underscore the critical role of microglia in neurodevelopment and their potential impact on neurodevelopmental disorders, emphasizing the need for further research into their mechanisms of action during brain development.

Microglia are increasingly recognized for their role in cancer biology, particularly in the context of glioblastoma. Li et al. demonstrate that β2-microglobulin (B2M) maintains glioblastoma stem cells and induces M2-like polarization of tumor-associated macrophages, thereby promoting a tumor-friendly microenvironment (ref: Li doi.org/10.1158/0008-5472.CAN-22-0507/). This study highlights the complex interactions between tumor cells and the immune microenvironment, suggesting that microglial polarization can significantly influence tumor progression and response to therapy. Additionally, Jiang et al. explore the role of NFAT1 in regulating microglial proliferation and transcription in the context of nerve injury-induced neuropathic pain, indicating that similar mechanisms may be at play in the tumor microenvironment (ref: Jiang doi.org/10.1002/advs.202201300/). The modulation of microglial activity through various signaling pathways presents a promising therapeutic avenue for targeting glioblastoma and potentially other cancers. Furthermore, Piec et al. investigate the effects of muramyl dipeptide on Alzheimer's disease, suggesting that innate immune modulation can also have implications for cancer biology, particularly in the context of neuroinflammation (ref: Piec doi.org/10.3390/cells11142241/). Collectively, these studies emphasize the dual role of microglia in both supporting tumor growth and influencing neurodegenerative processes, highlighting their potential as therapeutic targets in cancer treatment.

Microglia are integral to the mechanisms underlying pain and stress responses in the CNS. Abe et al. investigate the pathogenic neuropsychiatric effects of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus, revealing how stress can exacerbate neuropsychiatric symptoms through microglial activation (ref: Abe doi.org/10.1136/ard-2022-222566/). This study underscores the importance of microglial activation in mediating the effects of stress on brain function and behavior. Furthermore, Jiang et al. explore the role of NFAT1 in promoting microglial proliferation and transcription in the context of nerve injury-induced neuropathic pain, suggesting that microglial activation is a key component of pain pathways (ref: Jiang doi.org/10.1002/advs.202201300/). The findings indicate that targeting microglial activation could provide new therapeutic strategies for managing pain. Additionally, Piec et al. highlight the potential of muramyl dipeptide in delaying Alzheimer's disease physiopathology, suggesting that modulation of microglial responses can also influence stress-related outcomes (ref: Piec doi.org/10.3390/cells11142241/). Collectively, these studies emphasize the critical role of microglia in pain and stress mechanisms, highlighting their potential as therapeutic targets for alleviating pain and improving mental health outcomes.

Microglia play a crucial role in aging and neuroprotection, influencing the onset and progression of neurodegenerative diseases. Abe et al. investigate the pathogenic effects of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus, revealing how stress can exacerbate neuropsychiatric symptoms through microglial activation (ref: Abe doi.org/10.1136/ard-2022-222566/). This study highlights the importance of microglial activation in mediating the effects of stress on brain function and behavior, particularly in aging populations. Jiang et al. further explore the role of NFAT1 in orchestrating microglial transcription and promoting proliferation, linking these processes to nerve injury-induced neuropathic pain (ref: Jiang doi.org/10.1002/advs.202201300/). The findings suggest that microglial activation is a key component of neuroprotective mechanisms, particularly in response to injury. Additionally, Piec et al. highlight the potential of muramyl dipeptide in delaying Alzheimer's disease physiopathology, suggesting that modulation of microglial responses can have protective effects against neurodegeneration (ref: Piec doi.org/10.3390/cells11142241/). Collectively, these studies emphasize the critical role of microglia in aging and neuroprotection, highlighting their potential as therapeutic targets for promoting brain health in aging populations.