Microglia, the resident immune cells of the central nervous system, exhibit complex functions that are crucial for maintaining brain homeostasis and responding to injury. Recent studies have highlighted the importance of local translation in microglial processes, particularly in their ability to efficiently phagocytose pathogens. Vasek et al. demonstrated that peripheral microglial processes (PeMPs) contain ribosomes capable of de novo protein synthesis, which is essential for their motility and phagocytic functions (ref: Vasek doi.org/10.1038/s41593-023-01353-0/). Furthermore, the transcription factor SALL1 has been identified as a key regulator of microglial identity, with Fixsen et al. showing that disruption of a microglia-specific super-enhancer leads to a complete loss of SALL1 expression, underscoring its critical role in maintaining microglial characteristics (ref: Fixsen doi.org/10.1038/s41590-023-01528-8/). In addition, Yu et al. explored the turnover and lifespan of microglia, revealing that different origins of microglia exhibit distinct lifespans and self-renewal capabilities, which may influence their functional roles in the brain (ref: Yu doi.org/10.1126/sciadv.adf9790/). These findings collectively emphasize the dynamic nature of microglial function and identity, shaped by both intrinsic genetic factors and extrinsic environmental cues. Moreover, the role of fibrinogen in neuroinflammation has been elucidated, with evidence suggesting that it induces neurotoxic gene programs in microglia during neurodegenerative processes. The study by an unnamed author highlights how fibrinogen, often found in the brains of patients with neurological disorders, activates microglial responses that can lead to cognitive decline and impaired repair mechanisms (ref: Unknown doi.org/10.1038/s41590-023-01542-w/). Additionally, the involvement of border-associated macrophages (BAMs) in neuroinflammation related to Parkinson's disease has been characterized by Schonhoff et al., who demonstrated that BAMs are crucial for initiating CD4 T cell responses, while microglial MHCII loss does not significantly affect neuroinflammation (ref: Schonhoff doi.org/10.1038/s41467-023-39060-w/). This interplay between different immune cell types and their specific roles in neuroinflammatory contexts further complicates our understanding of microglial function and identity.

Microglia play a pivotal role in the pathogenesis of neurodegenerative diseases, with recent research uncovering various mechanisms through which they influence disease progression. Bouzid et al. investigated the association between clonal hematopoiesis of indeterminate potential (CHIP) and Alzheimer's disease (AD), finding that mutations in hematopoietic stem cells may alter myeloid cell function and potentially confer protection against AD (ref: Bouzid doi.org/10.1038/s41591-023-02397-2/). This suggests that genetic factors influencing myeloid cell development could be leveraged for therapeutic strategies in AD. In contrast, Tang et al. provided evidence that brain microglia serve as a persistent reservoir for HIV, even under antiretroviral therapy, highlighting their role in sustaining viral replication and contributing to neurocognitive disorders in HIV-infected individuals (ref: Tang doi.org/10.1172/JCI167417/). This underscores the dual role of microglia as both protectors and potential contributors to neurodegeneration. Furthermore, Sideris-Lampretsas et al. explored the role of galectin-3 in modulating microglial responses to inflammatory pain, revealing that wild-type mice exhibit a distinct microglial activation profile associated with inflammatory allodynia, while Alzheimer's disease model mice show reduced sensitivity (ref: Sideris-Lampretsas doi.org/10.1038/s41467-023-39077-1/). This suggests that microglial activation mechanisms may differ significantly across disease states, impacting pain perception and management. Additionally, Festa et al. reported that microglial cytokines can inhibit neuronal autophagy, linking neuroinflammation to the accumulation of toxic proteins in neurons, which is a hallmark of neurodegenerative diseases (ref: Festa doi.org/10.1080/15548627.2023.2221921/). Collectively, these studies illustrate the complex and often paradoxical roles of microglia in neurodegenerative diseases, where they can both protect and exacerbate neuronal damage.

The interplay between inflammation and immune responses in the central nervous system is critical for understanding various neurological conditions. Fibrinogen's role in neuroinflammation has been highlighted as it induces neurotoxic microglial gene programs, contributing to cognitive decline and impaired repair mechanisms in neurological diseases (ref: Unknown doi.org/10.1038/s41590-023-01542-w/). This study emphasizes the multifaceted role of fibrinogen in activating central nervous system inflammation, particularly in the context of blood-brain barrier disruption. Additionally, Schonhoff et al. investigated the role of border-associated macrophages (BAMs) in mediating neuroinflammatory responses in a model of Parkinson's disease, demonstrating that BAMs are essential for initiating CD4 T cell responses, while microglial MHCII loss does not significantly impact neuroinflammation (ref: Schonhoff doi.org/10.1038/s41467-023-39060-w/). This finding suggests that distinct immune cell populations may have specialized roles in orchestrating neuroinflammatory responses. Moreover, Sideris-Lampretsas et al. examined the activation of spinal microglia by galectin-3, revealing that this activation is linked to inflammatory nociception in wild-type mice but not in Alzheimer's disease models (ref: Sideris-Lampretsas doi.org/10.1038/s41467-023-39077-1/). This highlights the potential for differential microglial responses based on the underlying pathology. Furthermore, the research by Yang et al. on a reactive oxygen species-responsive nanoscavenger for promoting mitophagy in Alzheimer's disease underscores the therapeutic potential of targeting microglial activation and inflammatory pathways to enhance neuronal health (ref: Yang doi.org/10.1002/smll.202302284/). Together, these studies illustrate the critical role of inflammation and immune responses in shaping the outcomes of neurodegenerative diseases and highlight potential therapeutic avenues.

Microglial activation is a central feature in the pathophysiology of various neurological diseases, influencing disease mechanisms and outcomes. Tang et al. provided compelling evidence that brain microglia serve as a reservoir for HIV, maintaining viral persistence even during antiretroviral therapy (ref: Tang doi.org/10.1172/JCI167417/). This finding underscores the role of microglia in sustaining viral replication and their potential contribution to neurocognitive disorders in HIV-infected individuals. Additionally, Sideris-Lampretsas et al. explored the activation of spinal microglia by galectin-3, revealing that this activation is associated with inflammatory nociception in wild-type mice but not in Alzheimer's disease models, suggesting a differential response based on the underlying pathology (ref: Sideris-Lampretsas doi.org/10.1038/s41467-023-39077-1/). This highlights the complexity of microglial activation and its implications for pain perception in neurodegenerative diseases. Moreover, the study by Schonhoff et al. on border-associated macrophages (BAMs) in Parkinson's disease demonstrated their essential role in mediating neuroinflammatory responses, particularly in initiating CD4 T cell responses, while microglial MHCII loss had no significant impact on neuroinflammation (ref: Schonhoff doi.org/10.1038/s41467-023-39060-w/). This suggests that distinct immune cell populations may have specialized roles in orchestrating neuroinflammatory responses. Furthermore, Campbell et al. reported that HIV-1 Tat upregulates TREM1 expression in human microglia, contributing to their resistance to HIV-induced apoptosis, which poses challenges for HIV cure strategies (ref: Campbell doi.org/10.4049/jimmunol.2300152/). Collectively, these studies illustrate the multifaceted roles of microglial activation in disease mechanisms, highlighting their potential as therapeutic targets in neurodegenerative and infectious diseases.

Identifying therapeutic targets in microglial research is crucial for developing effective interventions for neurodegenerative diseases. Tang et al. highlighted the role of brain microglia as a persistent reservoir for HIV, emphasizing the need for strategies that can effectively target these cells to eliminate viral reservoirs and mitigate neurocognitive decline (ref: Tang doi.org/10.1172/JCI167417/). This underscores the importance of understanding microglial biology in the context of HIV infection and the potential for targeted therapies that can disrupt viral persistence. Additionally, Schonhoff et al. demonstrated that border-associated macrophages (BAMs) play a critical role in mediating neuroinflammatory responses in Parkinson's disease, suggesting that targeting these cells could enhance immune responses and improve disease outcomes (ref: Schonhoff doi.org/10.1038/s41467-023-39060-w/). Furthermore, Campbell et al. explored the upregulation of TREM1 in HIV-infected human microglia, revealing that this receptor contributes to their resistance to HIV-induced apoptosis (ref: Campbell doi.org/10.4049/jimmunol.2300152/). Targeting TREM1 could potentially enhance the efficacy of HIV treatments by promoting apoptosis in infected microglia. Sideris-Lampretsas et al. also investigated the role of galectin-3 in activating spinal microglia, linking this activation to inflammatory nociception in wild-type mice, which may provide insights into pain management strategies in neurodegenerative diseases (ref: Sideris-Lampretsas doi.org/10.1038/s41467-023-39077-1/). Overall, these studies highlight the potential of targeting specific microglial pathways and receptors as promising therapeutic strategies for various neurological disorders.

Microglia play a significant role in the neuroinflammatory response following ischemic stroke, influencing recovery and outcomes. Wang et al. demonstrated that microglia-mediated neuroimmune responses regulate sympathetic neuron activity and cardiac remodeling after myocardial infarction, suggesting that microglial activation can have systemic effects beyond the central nervous system (ref: Wang doi.org/10.1161/JAHA.122.029053/). This highlights the importance of understanding microglial functions in the context of cardiovascular events and their potential impact on brain health. Additionally, Otsu et al. investigated the effects of oxygen-glucose deprived peripheral blood mononuclear cells (OGD-PBMCs) on ischemic stroke, revealing that these cells promote angiogenesis and axonal outgrowth, leading to functional recovery after cerebral ischemia (ref: Otsu doi.org/10.1007/s13311-023-01398-w/). This suggests that modulating the microenvironment through immune cell interventions could enhance recovery following stroke. Moreover, Yang et al. explored the role of Netrin-1 in regulating microglial phenotypes in response to ischemic stroke, indicating that targeting microglial pathways could provide new therapeutic avenues for enhancing neuronal survival and regeneration (ref: Yang doi.org/10.3389/fimmu.2023.1178638/). These findings collectively underscore the critical role of microglia in mediating neuroinflammation and recovery processes following stroke, highlighting their potential as therapeutic targets for improving outcomes in stroke patients.

Microglial interactions with other cell types are crucial for understanding their role in neuroinflammation and disease. Campbell et al. investigated the upregulation of TREM1 in HIV-infected human microglia, revealing that this receptor contributes to their resistance to HIV-induced apoptosis, which poses challenges for HIV cure strategies (ref: Campbell doi.org/10.4049/jimmunol.2300152/). This highlights the complex interplay between microglia and viral infections, suggesting that targeting microglial responses could enhance treatment efficacy. Additionally, Schonhoff et al. characterized the role of border-associated macrophages (BAMs) in mediating neuroinflammatory responses in a model of Parkinson's disease, demonstrating that BAMs are essential for initiating CD4 T cell responses, while the loss of MHCII antigen presentation on microglia had no significant effect on neuroinflammation (ref: Schonhoff doi.org/10.1038/s41467-023-39060-w/). This suggests that distinct immune cell populations may have specialized roles in orchestrating neuroinflammatory responses. Furthermore, Sideris-Lampretsas et al. examined the activation of spinal microglia by galectin-3, linking this activation to inflammatory nociception in wild-type mice but not in Alzheimer's disease models (ref: Sideris-Lampretsas doi.org/10.1038/s41467-023-39077-1/). This indicates that microglial responses can vary significantly depending on the surrounding cellular environment and disease context. Collectively, these studies illustrate the importance of understanding microglial interactions with other cell types in shaping immune responses and disease outcomes, highlighting potential therapeutic targets for modulating these interactions.