The nervous system processes a vast amount of information, performing computations that underlie perception, cognition, and behavior. During development, neuronal guidance genes, which encode extracellular cues, their receptors, and downstream signal transducers, organize neural wiring to generate the complex architecture of the nervous system. It is now evident that many of these neuroguidance cues and their receptors are active during development and are also expressed in the adult nervous system. This suggests that neuronal guidance pathways are critical not only for neural wiring but also for ongoing function and maintenance of the mature nervous system. Supporting this view, these pathways continue to regulate synaptic connectivity, plasticity, and remodeling, and overall brain homeostasis throughout adulthood. Genetic and transcriptomic analyses have further revealed many neuronal guidance genes to be associated with a wide range of neurodegenerative and neuropsychiatric disorders. Although the precise mechanisms by which aberrant neuronal guidance signaling drives the pathogenesis of these diseases remain to be clarified, emerging evidence points to several common themes, including dysfunction in neurons, microglia, astrocytes, and endothelial cells, along with dysregulation of neuron-microglia-astrocyte, neuroimmune, and neurovascular interactions. In this review, we explore recent advances in understanding the molecular and cellular mechanisms by which aberrant neuronal guidance signaling contributes to disease pathogenesis through altered cell-cell interactions. For instance, recent studies have unveiled two distinct semaphorin-plexin signaling pathways that affect microglial activation and neuroinflammation. We discuss the challenges ahead, along with the therapeutic potentials of targeting neuronal guidance pathways for treating neurodegenerative diseases. Particular focus is placed on how neuronal guidance mechanisms control neuron-glia and neuroimmune interactions and modulate microglial function under physiological and pathological conditions. Specifically, we examine the crosstalk between neuronal guidance signaling and TREM2, a master regulator of microglial function, in the context of pathogenic protein aggregates. It is well-established that age is a major risk factor for neurodegeneration. Future research should address how aging and neuronal guidance signaling interact to influence an individual's susceptibility to various late-onset neurological diseases and how the progression of these diseases could be therapeutically blocked by targeting neuronal guidance pathways.

Brain organoids encompass a large collection of in vitro stem cell-derived 3D culture systems that aim to recapitulate multiple aspects of in vivo brain development and function. First, this review provides a brief introduction to the current state-of-the-art for neuro-ectoderm brain organoid development, emphasizing their biggest advantages in comparison with classical two-dimensional cell cultures and animal models. However, despite their usefulness for developmental studies, a major limitation for most brain organoid models is the absence of contributing cell types from endodermal and mesodermal origin. As such, current research is highly investing towards the incorporation of a functional vasculature and the microglial immune component. In this review, we will specifically focus on the development of immune-competent brain organoids. By summarizing the different approaches applied to incorporate microglia, it is highlighted that immune-competent brain organoids are not only important for studying neuronal network formation, but also offer a clear future as a new tool to study inflammatory responses in vitro in 3D in a brain-like environment. Therefore, our main focus here is to provide a comprehensive overview of assays to measure microglial phenotype and function within brain organoids, with an outlook on how these findings could better understand neuronal network development or restoration, as well as the influence of physical stress on microglia-containing brain organoids. Finally, we would like to stress that even though the development of immune-competent brain organoids has largely evolved over the past decade, their full potential as a pre-clinical tool to study novel therapeutic approaches to halt or reduce inflammation-mediated neurodegeneration still needs to be explored and validated.

Microglia, the central nervous system (CNS) resident immune cells, are pivotal in regulating neurodevelopment, maintaining neural homeostasis, and mediating neuroinflammatory responses. Recent research has highlighted the importance of mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, in regulating microglial activity. Among the various mechanosensitive channels, Piezo1 has emerged as a key player in microglia, influencing their behavior under both physiological and pathological conditions. This review focuses on the expression and role of Piezo1 in microglial cells, particularly in the context of neuroinflammation and tumorigenesis. We explore how Piezo1 mediates microglial responses to mechanical changes within the CNS, such as alterations in tissue stiffness and fluid shear stress, which are common in conditions like multiple sclerosis, Alzheimer's disease, cerebral ischemia, and gliomas. The review also discusses the potential of targeting Piezo1 for therapeutic intervention, given its involvement in the modulation of microglial activity and its impact on disease progression. This review integrates findings from recent studies to provide a comprehensive overview of Piezo1's mechanistic pathways in microglial function. These insights illuminate new possibilities for developing targeted therapies addressing CNS disorders with neuroinflammation and pathological tissue mechanics.

Depression includes different phenotypes. Modern-type depression (MTD) is a gateway disorder to pathological social withdrawal, known as hikikomori. Adverse childhood experiences (ACEs) are also important aetiologies of depression. Recently, immune imbalance has been proposed as a biological basis of depression. We hypothesised that peripheral immunological characteristics may be involved in subtyping of depression.

21 patients with major depressive disorder (MDD) and 24 healthy controls (HC) were recruited. Peripheral blood mononuclear cells (PBMCs) were examined for surface antigens by flow cytometry. Participants were administered psychological scales such as Patient Health Questionnaire (PHQ)-9, Modern-Type Depression Trait Scale (TACS-22), Hikikomori Questionnaire (HQ-25), Child Abuse and Trauma Scale (CATS).

MDD group showed significantly higher percentage of B cells than HC group (p = 0.032). MDD group presented a negative correlation between: PHQ-9 and CD8 T effector memory cells (r= -0.639, p = 0.002), TACS-22 and monocytes (r= -0.459, p = 0.036), HQ-25 and NK T cells (r= -0.638, p = 0.004), CATS and Intermediate monocytes (r= -0.594, p = 0.009).

MTD traits, hikikomori tendencies, and ACEs were correlated with specific characteristics of peripheral immune cells. Our results suggest that immune imbalance influences the diverse presentations of depression. Further validation is warranted by large-scale prospective studies.

Subarachnoid hemorrhage leads to a series of pathological changes, including vascular spasm, cellular apoptosis, blood-brain barrier damage, cerebral edema, and white matter injury. Microglia, which are the key immune cells in the central nervous system, maintain homeostasis in the neural environment, support neurons, mediate apoptosis, participate in immune regulation, and have neuroprotective effects. Increasing evidence has shown that microglia play a pivotal role in the pathogenesis of subarachnoid hemorrhage and affect the process of injury and the prognosis of subarachnoid hemorrhage. Moreover, microglia play certain neuroprotective roles in the recovery phase of subarachnoid hemorrhage. Several approaches aimed at modulating microglia function are believed to attenuate subarachnoid hemorrhage injury. This provides new targets and ideas for the treatment of subarachnoid hemorrhage. However, an in-depth and comprehensive summary of the role of microglia after subarachnoid hemorrhage is still lacking. This review describes the activation of microglia after subarachnoid hemorrhage and their roles in the pathological processes of vasospasm, neuroinflammation, neuronal apoptosis, blood-brain barrier disruption, cerebral edema, and cerebral white matter lesions. It also discusses the neuroprotective roles of microglia during recovery from subarachnoid hemorrhage and therapeutic advances aimed at modulating microglial function after subarachnoid hemorrhage. Currently, microglia in subarachnoid hemorrhage are targeted with TLR inhibitors, nuclear factor-κB and STAT3 pathway inhibitors, glycine/tyrosine kinases, NLRP3 signaling pathway inhibitors, Gasdermin D inhibitors, vincristine receptor α receptor agonists, ferroptosis inhibitors, genetic modification techniques, stem cell therapies, and traditional Chinese medicine. However, most of these are still being evaluated at the laboratory stage. More clinical studies and data on subarachnoid hemorrhage are required to improve the treatment of subarachnoid hemorrhage.

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms. Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration. However, recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration, particularly in the context of traumatic injuries. Consequently, autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration. Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths, thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation. These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration. A range of autophagy-inducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries. This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration, summarizing the potential drugs and interventions that can be harnessed to promote this process. We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

Depression is a globally prevalent emotional disorder with a complex pathophysiology. Microglia are resident immune cells in the central nervous system, playing crucial roles in regulating inflammation, synaptic plasticity, immune phagocytosis, and other functions, thereby exerting significant impacts on neuropsychiatric disorders like depression. Increasing research indicates that abnormal phagocytic function of microglia in the brain is involved in depression, showing excessive or insufficient phagocytosis in different states. Here, we have provided a review of the signaling molecules involved in microglial phagocytosis in depression, including "eat me" signals such as phosphatidylserine (PS), complement, and "don't eat me" signals such as CD47, CD200 and related receptors. Furthermore, we discuss the regulatory effects of existing pharmaceuticals and dietary nutrients on microglial phagocytosis in depression, emphasizing the need for tailored modulation based on the varying phagocytic states of microglia. This review aims to facilitate a deeper understanding of the role of microglial phagocytosis in depression and provide a roadmap for potential therapeutic strategies for depression targeting microglial phagocytosis.

The triggering receptors expressed on myeloid cells (TREMs) family of cell surface receptors are mainly expressed by myeloid cells. The expression profile of TREM-like 2 (TREML2), a TREM family member, in patients with acute myeloid leukemia (AML) is unknown. In this study, we aimed to elucidate the role of TREML2 in the development of AML. We analyzed the TREML2 expression profile in patients with AML. TREML2 was expressed at lower levels in patients with AML than in healthy individuals. The partial remission (PR) + no remission (NR) group showed lower TREML2 expression levels and a poorer chemotherapy response than that observed in the complete remission group. Overall survival was significantly shorter in the group with low TREML2 expression levels than in the group with high TREML2 expression levels. TREML2 inhibited the proliferation of AML cells and enhanced the sensitivity of AML cells to doxorubicin. Mechanistically, TREML2 reduced C-X-C motif chemokine ligand 10 expression levels by inhibiting the nuclear factor kappa B pathway. Taken together, we demonstrate that TREML2 has diagnostic value as a potential indicator of AML and that upregulation of TREML2 may be a new strategy to overcome doxorubicin resistance for AML treatment.

Non-neuronal cells constitute a significant portion of brain tissue and are seen as having key roles in brain homeostasis and responses to challenges. This review illustrates how non-neuronal biology can bring new perspectives to animal welfare through understanding mechanisms that determine welfare outcomes and highlighting interventions to improve welfare. Most obvious in this respect is the largely unrecognised relevance of neuroinflammation to animal welfare which is increasingly found to have roles in determining how animals respond to challenges. We start by introducing non-neuronal cells and review their involvement in affective states and cognition often seen as core psychological elements of animal welfare. We find that the evidence for a causal involvement of glia in cognition is currently more advanced than the corresponding evidence for affective states. We propose that translational research on affective disorders could usefully apply welfare science derived approaches for assessing affective states. Using evidence from translational research, we illustrate the involvement of non-neuronal cells and neuroinflammatory processes as mechanisms modulating resilience to welfare challenges including disease, pain, and social stress. We review research on impoverished environments and environmental enrichment which suggests that environmental conditions which improve animal welfare also improve resilience to challenges through balancing pro- and anti-inflammatory non-neuronal processes. We speculate that non-neuronal biology has relevance to animal welfare beyond neuro-inflammation including facilitating positive affective states. We acknowledge the relevance of neuronal biology to animal welfare whilst proposing that non-neuronal biology provides additional and relevant insights to improve animals' lives.

Traumatic brain injury (TBI) is a leading cause of long-term disability worldwide, with secondary injury mechanisms, including neuroinflammation and oxidative stress, driving much of its chronic pathology. While NADPH oxidase 2 (NOX2)-mediated reactive oxygen species (ROS) production is a recognized factor in TBI, the specific role of microglial NOX2 in perpetuating oxidative and inflammatory damage remains underexplored. Addressing this gap is critical, as current therapeutic approaches primarily target acute symptoms and fail to interrupt the persistent neuroinflammation that contributes to progressive neurodegeneration. Besides NOX, other ROS-generating enzymes, such as CYP1B1, COX2, and XO, also play crucial roles in triggering oxidative stress and neuroinflammatory conditions in TBI. However, this review highlights the pathophysiological role of microglial NOX2 in TBI, focusing on its activation following injury and its impact on ROS generation, neuroinflammatory signaling, and neuronal loss. These insights reveal NOX2 as a critical driver of secondary injury, linked to worsened outcomes, particularly in aged individuals where NOX2 activation is more pronounced. In addition, this review evaluates emerging therapeutic approaches targeting NOX2, such as GSK2795039 and other selective NOX2 inhibitors, which show potential in reducing ROS levels, limiting neuroinflammation, and preserving neurological functions. By highlighting the specific role of NOX2 in microglial ROS production and secondary neurodegeneration, this study advocates for NOX2 inhibition as a promising strategy to improve TBI outcomes by addressing the unmet need for therapies targeting long-term inflammation and neuroprotection. Our review highlights the potential of NOX2-targeted interventions to disrupt the cycle of oxidative stress and inflammation, ultimately offering a pathway to mitigate the chronic impact of TBI.

CD163 is a scavenger receptor predominantly expressed on the surfaces of macrophages in various mammalian species and is a marker of anti-inflammatory (M2-like) macrophages. High density of CD163-positive tumor-associated macrophages (TAMs) is associated with worse prognosis in various patient tumors. Interestingly, studies on mice have shown that CD163-positive TAMs only infiltrate the margins of tumor tissues, not the center. Based on these observations, we hypothesized that circulating monocyte-derived macrophages (MDMs), which are the origin of most TAMs, do not express CD163 in mice.

We examined CD163 expression in MDMs, differentiated from healthy animals in vitro, and in normal, pathogenic, and tumorigenic macrophages infiltrating various tumors and organs across multiple species including primates, rodents, cetartiodactylans, and carnivores. We found that MDMs, including TAMs, do not express CD163 in mice. Our findings also suggest that murine CD163-positive macrophages likely originate from a specific subset of resident macrophages, namely fetal liver monocytes/macrophages, as indicated by fetal analysis. Furthermore, we revealed that the CD163-negative expression pattern in MDMs is a trait shared by the rodent clade.

Rodent MDMs do not express CD163, a phenotype not shared with MDMs of other mammals. Our findings caution against the extrapolation of rodent experimental results to other animal models.

Multiple sclerosis is a biologically and clinically heterogenous inflammatory demyelinating disease, driven by relapsing and progressive mechanisms, all individuals experiencing varying degrees of both. Existing highly effective therapies target peripheral inflammation and reduce relapse rates but have limited efficacy in progressive MS due to poor blood-brain barrier penetration and inability to address neurodegeneration. Bruton's tyrosine kinase (BTK) inhibitors represent an emerging therapeutic class offering a novel mechanism targeting BTK, which is expressed by both B cells and myeloid cells, including microglia within the CNS. Pre-clinical, Phase II, and Phase III clinical trials have demonstrated promising results in modulating progressive disease in both relapsing and non-relapsing MS patients. In contrast, the evidence regarding impact on relapse biology remains mixed and somewhat inconclusive. This review highlights gaps in current therapeutic strategies, examines the latest evidence for the efficacy and safety of BTK inhibitors in MS, and explores the future landscape of MS treatment.

Pain is entwined with inflammation, and biological sex often influences mechanisms of the immune system. Due to possible differences in inflammatory mechanisms, women are predisposed to autoimmune diseases and chronic pain. Despite sex as a critical variable in clinical cases of autoimmune conditions and its pain comorbidities, fundamental investigations have long underrepresented female subjects in their studies. Fundamental research in the 2010 s, however, identified a binary sex specific mechanism for pain in rodents: male pain is microglia-driven while female pain is T cell-driven. Since then, studies have expanded in neuro-immunology to indicate that the sex differences and immune cells involved in these processes take on more elaborate roles when expanded to other causal modalities and anatomical levels of neuropathic and inflammatory pain. In this mini-review, we highlight updated roles for macrophages, T cells, and B cells in the peripheral nervous system during persistent pain conditions: neuropathic pain and inflammatory pain. We discuss sex similarities and sex differences in these cell types. By parsing out the sex specific roles of immune cells in persistent pain states we may be better positioned to find immune-based therapies that can effectively target chronic pain in sex-biased autoimmune conditions.

The adult mammalian brain exhibits remarkable forms of neural plasticity, enabling it to adapt and reorganize in response to internal and external stimuli. These plastic mechanisms include cytogenesis, the capacity of producing new neuronal and glial cells in restricted brain regions through processes known as neuro- and gliogenesis, respectively. Although many advances have been made in understanding adult brain plastic processes associated with cell genesis, as well as its functional and behavioral implications, most of the evidence is focused on neuronal cells. Even though astrocytes play a critical role in maintaining a neurochemical and electrophysiological homeostasis in the brain and provide a pivotal support to neuronal activity, the molecular mechanisms underlying the formation and functional integration of newly formed astroglial cells are poorly understood. However, some studies have provided key insights into the molecular mechanisms driving the generation of adult neural stem cell (NSC)-derived astrocytes, focusing on the dentate gyrus of the hippocampal cytogenic niche. Recent work has demonstrated that intrinsic and extrinsic factors can modulate astrogliogenesis. In the context of neuropathogenesis, this mechanism may be compromised in the hippocampus, contributing to functional and behavioral impairments. Here, we review the mechanisms underlying NSC-derived hippocampal astrogliogenesis, examining current perspectives on how adult-born astrocytes develop in the adult brain, their functional relevance, and the intricate regulation of the astrogliogenic process.

Blood vessels are critical to deliver oxygen and nutrients to tissues and organs throughout the body. The blood vessels that vascularize the central nervous system (CNS) possess unique properties, termed the blood-brain barrier (BBB), which allow these vessels to tightly regulate the movement of ions, molecules, and cells between the blood and the brain. This precise control of CNS homeostasis allows for proper neuronal function and protects the neural tissue from toxins and pathogens, and alterations of this barrier are important components of the pathogenesis and progression of various neurological diseases. The physiological barrier is coordinated by a series of physical, transport, and metabolic properties possessed by the brain endothelial cells (ECs) that form the walls of the blood vessels. These properties are regulated by interactions between different vascular, perivascular, immune, and neural cells. Understanding how these cell populations interact to regulate barrier properties is essential for understanding how the brain functions in both health and disease contexts.

Parkinson's disease (PD), a prevalent neurodegenerative disorder, is linked to genetics and environment, but its mechanisms remain unclear. Emerging evidence connects purinergic signaling-particularly ATP-sensitive P2X7 receptor (P2X7R)-to PD. P2X7R expression is elevated in PD patients, and its antagonist BBG mitigates 6-OHDA-induced dopaminergic neuron death. This review discusses P2X7R's structure, neural functions, PD-related mechanisms, and therapeutic potential as a targert.

The central nervous system (CNS) can be subdivided into distinct anatomical and functional compartments, including the parenchyma, perivascular space, leptomeninges, and dura mater, etc. Each compartment hosts distinct immune cell populations, such as monocytes and diverse macrophages, which play critical roles in local tissue homeostasis and regional disease pathogenesis. Advances in single-cell technologies have revealed complex immune cell compositions and functions in these anatomical regions. This review summarizes the latest approaches for modulating myeloid cell subsets in a compartment-specific manner, including cellular strategies such as stem cell therapy, ex vivo gene treatment, bone marrow transplantation, as well as non-cellular strategies like antibodies, small molecules, and viral gene delivery to augment CNS immune responses and improve disease outcomes. We also discuss the challenges and requirements of translating targeting strategies from mice to humans.

Tumor-associated macrophages (TAMs) play a pivotal role in the tumor microenvironment (TME), actively contributing to the formation of an immunosuppressive niche that fosters tumor progression. Consequently, there has been a growing interest in targeting TAMs as a promising avenue for cancer therapy. Recent advances in the field of immunometabolism have shed light on the influence of metabolic adaptations on macrophage physiology in the context of cancer. Here, we discuss the key metabolic pathways that shape the phenotypic diversity of macrophages. We place special emphasis on how metabolic reprogramming impacts the activation status of TAMs and their functions within the TME. Additionally, we explore alterations in TAM metabolism and their effects on phagocytosis, production of cytokines/chemokines and interaction with cytotoxic T and NK immune cells. Moreover, we examine the application of nanomedical approaches to target TAMs and assess the clinical significance of modulating the metabolism of TAMs as a strategy to develop new anti-cancer therapies. Taken together, in this comprehensive review article focusing on TAMs, we provide invaluable insights for the development of effective immunotherapeutic strategies and the enhancement of clinical outcomes for cancer patients.

Glioblastoma is the most aggressive and lethal cancer of the central nervous system, presenting substantial treatment challenges. The current standard treatment, which includes surgical resection followed by temozolomide and radiation, offers limited success. While immunotherapies, such as immune checkpoint inhibitors, have proven effective in other cancers, they have not demonstrated significant efficacy in GBM. Emerging research highlights the pivotal role of tumor-associated macrophages (TAMs) in supporting tumor growth, fostering treatment resistance, and shaping an immunosuppressive microenvironment. Preclinical studies show promising results for therapies targeting TAMs, suggesting potential in overcoming these barriers. TAMs consist of brain-resident microglia and bone marrow-derived macrophages, both exhibiting diverse phenotypes and functions within the tumor microenvironment. This review delves into the origin, heterogeneity, and functional roles of TAMs in GBM, underscoring their dual roles in tumor promotion and suppression. It also summarizes recent progress in TAM-targeted therapies, which may, in combination with other treatments like immunotherapy, pave the way for more effective and personalized strategies against this aggressive malignancy.

Rich neural-immune interactions in the central nervous system (CNS) shape its function and create a unique immunological microenvironment for immunotherapy in CNS malignancies. Far from the now-debunked concept of CNS "immune privilege," it is now understood that unique immunological niches and constant immune surveillance of the brain contribute in multifaceted ways to brain health and robustly influence immunotherapy approaches for CNS cancers. Challenges include immune-suppressive and neurotoxicity-promoting crosstalk between brain, immune, and tumor cells. Developing effective immunotherapies for cancers of the nervous system will require a deeper understanding of these neural-immune-malignant cell interactions. Here, we review progress and challenges in immunotherapy for gliomas of the brain and spinal cord in light of these unique neural-immune interactions and highlight future work needed to optimize promising immunotherapies for gliomas.

Microglia are the brain resident macrophages that respond rapidly to any insult. These non-neuroectodermal cells are decorated with plenty of receptors allowing them to recognise and respond precisely to a multitude of stimuli. To do so, microglia undergo structural and functional changes aiming to actively keep the brain's homeostasis. However, some microglial responses, when sustained or exacerbated, can contribute to neuropathology and neurodegeneration. Many microglial molecular and cellular changes were identified that display a strong correlation with neuronal damage and neuroinflammation/disease status, as well as present key sex-related differences that modulate microglial outcomes. Nevertheless, the relationship between microglial structural and functional features is just beginning to be unravelled. Several reports show that microglia undergo soma and branch remodelling in response to environmental stimuli, ageing, neurodegenerative diseases, trauma, and systemic inflammation, suggesting a complex form and function link. Also, it is reasonable overall to suppose that microglia diminishing their process length and ramification also reduce their monitoring activity of synapses, which is critical for detecting any synaptic disturbance and performing synaptic remodelling. Elucidating the complex interactions between microglial morphological plasticity and its functional implications appears essential for the understanding of complex cognitive and behavioural processes in health and neuropathological conditions.

Neuropathic pain is a debilitating condition caused by damage to the nervous system that results in changes along the pain pathway that lead to persistence of the pain sensation. Unremitting pain conditions are associated with maladaptive plasticity, disruption of neuronal activity that favours excitation over inhibition, and engagement of immune cells. The substantial progress made over the last two decades in the neuroimmune interaction research area points to a mechanistic role of spinal cord microglia, which are resident immune cells of the CNS. Microglia respond to and modulate neuronal activity during establishment and persistence of neuropathic pain states, and microglia-neuron pathways provide targets that can be exploited to attenuate abnormal neuronal activity and provide pain relief.

Genome-wide association studies have been remarkably successful in identifying genetic variants associated with age-related macular degeneration (AMD), demonstrating a strong genetic component largely driven by common variants. However, progress in translating these genetic findings into a deeper understanding of disease mechanisms and new therapies has been slow. Slow progress in this area can be attributed to limited knowledge of the functional impact of AMD-associated non-coding variants on gene function, the molecular mechanisms and cell types underlying disease. This review offers a comprehensive overview of functional genomics approaches to uncover the genetic, epigenetic, cellular and molecular mechanisms underlying AMD and outlines future directions for research.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients.

Brain organoids are an emerging in vitro 3D brain model that is integrated from pluripotent stem cells. This model mimics the human brain's developmental process and disease-related phenotypes to a certain extent while advancing the development of human brain-based biological intelligence. However, many limitations of brain organoid culture (e.g., lacking a functional vascular system, etc.) prevent in vitro-cultured organoids from truly replicating the human brain in terms of cell type and structure. To improve brain organoids' scalability, efficiency, and stability, this paper discusses important contributions of material biology and microprocessing technology in solving the related limitations of brain organoids and applying the latest imaging technology to make real-time imaging of brain organoids possible. In addition, the related applications of brain organoids, especially the development of organoid intelligence combined with artificial intelligence, are analyzed, which will help accelerate the rational design and guidance of brain organoids.

Microglia depletion, followed by repopulation, improves cognitive functions in the aged mouse brain. However, even temporal ablation of microglia puts the brain at a high risk of infection. Hence, in the present work, we studied if the partial reduction of microglia with PLX3397 (pexidartinib), an inhibitor of the colony-stimulating factor 1 receptor (CSF1R), could bring similar benefits as reported for microglia ablation. Aged (two-years-old) mice were treated with PLX3397 for a total of 6 weeks, which reduced microglia numbers in the hippocampus and retrosplenial cortex (RSC) to the levels seen in young mice and resulted in layer-specific ablation in the expression of microglial complement protein C1q mediating synaptic remodeling. This treatment boosted long-term potentiation in the CA1 region and improved performance in the hippocampus-dependent novel object location recognition task. Although PLX3397 treatment did not alter the number or total intensity of Wisteria floribunda agglutinin-positive perineuronal nets (PNNs) in the CA1 region of the hippocampus, it changed the fine structure of PNNs. It also elevated the expression of perisynaptic proteoglycan brevican, presynaptic vGluT1 at excitatory synapses, and vGAT in inhibitory ones in the CA1 stratum radiatum. Thus, targeting the CSF1R may provide a safe and efficient strategy to boost synaptic and cognitive functions in the aged brain.

Pancreatic ductal adenocarcinoma (PDAC) is one of the few cancers that has yet to benefit from immunotherapies. This is primarily a result of its characteristic 'cold' tumor microenvironment composed of cancer-associated fibroblasts (CAFs), a dense network of extracellular matrix and several immune cell types, the most abundant of which are the tumor-associated macrophages (TAMs). Advances in single-cell and spatial technologies have elucidated the vast functional heterogeneity of CAFs and TAMs, their symbiotic relationship and their cooperative role in the tumor microenvironment. In this Review, we provide an overview of the heterogeneity of CAFs and TAMs, how they establish an immunosuppressive microenvironment and their collaboration in the remodeling of the extracellular matrix. Finally, we examine why the impact of immunotherapy in PDAC has been limited and how a detailed molecular and spatial understanding of the combined role of CAFs and TAMs is paramount to the design of effective therapies.

Immune processes have been implicated in the pathophysiology of autism spectrum disorder (ASD). Brain borders, such as the skull, have recently been highlighted as sites where neuro-immune interactions occur with key consequences for brain immunity. Translocator protein (TSPO), a mitochondrial protein involved in immune functions, was measured in the skull using [11C]PBR28 positron emission tomography-magnetic resonance imaging (PET-MRI) in 38 autistic adults (26 males, 12 females) and 29 age-and sex-matched healthy controls (19 males, 10 females). [11C]PBR28 uptake relative to a pseudo-reference region assessed using standardized uptake value ratio (SUVR) revealed elevated TSPO in autistic adults in frontal and temporal skull. We did not observe an association between [11C]PBR28 uptake in total or regional skull areas and autism symptom severity. C-reactive protein levels were positively associated with [11C]PBR28 uptake in the total skull across participants. Lastly, [11C]PBR28 uptake in the total skull was stable across a 4-month period. This work indicates regional TSPO elevations in the skull in autistic adults, which may suggest immune involvement.

The complex interplay between the immune and cardiovascular systems during development, homeostasis and regeneration represents a rapidly evolving field in cardiac biology. Single cell technologies, spatial mapping and computational analysis have revolutionised our understanding of the diversity and functional specialisation of immune cells within the heart. From the earliest stages of cardiogenesis, where primitive macrophages guide heart tube formation, to the complex choreography of inflammation and its resolution during regeneration, immune cells emerge as central orchestrators of cardiac fate. Translating these fundamental insights into clinical applications represents a major challenge and opportunity for the field. In this Review, we decode the immunological blueprint of heart development and regeneration to transform cardiovascular disease treatment and unlock the regenerative capacity of the human heart.

Microglia are the primary resident immune cells of the central nervous system (CNS) that respond to injury and infections. Being critical to CNS homeostasis, microglia also have been shown to contribute to neurodegenerative diseases and brain cancer. Hence, microglia are regarded as a potential therapeutic target in CNS diseases, resulting in an increased demand for reliable in vitro models. Two human microglia cell lines (HMC3 and C20) are being used in multiple in vitro studies, however, the knowledge of their biological and immunological characteristics remains limited. Our aim was to identify and compare the biological changes in these immortalised immune cells under normal physiological and immunologically challenged conditions. Using high-resolution quantitative mass spectrometry, we have examined in-depth proteomic profiles of non-stimulated and LPS or IFN-γ challenged HMC3 and C20 cells. Our findings reveal that HMC3 cells responded to both treatments through upregulation of immune, metabolic, and antiviral pathways, while C20 cells showed a response associated with mitochondrial and immune activities. Additionally, the secretome analysis demonstrated that both cell lines release IL-6 in response to LPS, while IFN-γ treatment resulted in altered kynurenine pathway activity, highlighting distinct immune and metabolic adaptations.

Immunoglobulin E (IgE) is the most recently discovered and evolved mammalian antibody type, best known for interacting with mast cells (MCs) as immune effectors. IgE-mediated antigen sensing by MC provides protection from parasites, venomous animals, bacteria, and other insults to barrier tissues exposed to the environment. IgE and MCs act as inflammation amplifiers and immune response adjuvants. Thus, IgE production and memory formation are greatly constrained and require specific licensing. Failure of regulation gives rise to allergic disease, one of the top causes of chronic illness. Increasing evidence suggests allergy development often starts early in life, including prenatally, with maternal influence being central in shaping the offspring's immune system. Although IgE often exists before birth, an endogenous source of IgE-producing B cells has not been identified. This review discusses the mechanisms of maternal IgE transfer into the offspring, its interactions with offspring MCs and antigen-presenting cells, and the consequences for allergic inflammation and allergen sensitization development. We discuss the multifaceted effects of pre-existing IgG, IgE, and their glycosylation on maternal IgE transfer and functionality in the progeny. Understanding the IgE-mediated mechanisms predisposing for early life allergy development may allow their targeting with existing therapeutics and guide the development of new ones.

Microglia and border-associated macrophages (BAMs) are critical for brain health, and their dysfunction is associated to disease. Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Here, we demonstrate that monocytes can efficiently replace all brain macrophages. Monocytes readily replaced embryonal BAMs upon their depletion and engrafted as monocyte-derived microglia (Mo-Microglia) upon more sustained niche availability. Mo-Microglia expanded comparably to their embryonic counterparts and showed similar longevity. However, monocytes were unable to replicate the distinct identity of embryonically derived BAMs and microglia. Using xenotransplantation, we found that human monocytes exhibited similar behavior, enabling identification of putative Mo-Microglia in Alzheimer's disease individuals. In mice and humans, monocyte ontogeny shaped their identity as brain macrophages. Importantly, mouse fetal liver monocytes exhibited a distinct epigenetic landscape and could develop a bona fide microglial identity. Our results illuminate brain macrophage development and highlight monocytes as an abundant progenitor source for brain macrophage replacement therapies.

Recent evidence suggests that type I interferon (IFN-I) signalling extends beyond its canonical roles in antiviral defence and immunomodulation. Over the past decade, dysregulated IFN-I signalling has been linked to genetic disorders and neurodegenerative diseases, where it may contribute to neurological impairments. Microglia have emerged as key mediators of IFN-I responses in the central nervous system. A distinct transcriptional state responsive to interferons has recently been identified in microglia. The activation of the IFN-I pathway in these cells is now recognised as pivotal in both development and neurodegeneration. This review is divided into two main sections: the first examines the broader role of IFN-I signalling in the central nervous system, particularly its contribution to neurological dysfunction; the second focuses on the specific state of interferon-responsive microglia, exploring its mechanisms and relevance in neurodegenerative conditions. Finally, we discuss how these areas intersect and their implications for both healthy and diseased states.

Perivascular macrophages (PVMs) are a specialized subset of macrophages situated near blood vessels in the brain. Their strategic positioning around these vessels enables them to perform key functions in immune surveillance and response to inflammation and injury. These cells are crucial for modulating the immune response within the brain, contributing to normal central nervous system (CNS) processes. In pathological conditions, the role of PVMs becomes more complex. Depending on the specific disease or injury, they may contribute to inflammation, blood-brain barrier (BBB) dysfunction, and the clearance of abnormal materials. PVMs are implicated in degenerative diseases, cerebrovascular impairment, and microhemorrhages associated with amyloid-β immunotherapy. Despite their important roles in the CNS, research on PVMs remains limited, and the mechanisms underlying their involvement in both physiological and pathological processes within the brain are not yet fully elucidated. Therefore, this review will focus on the current advancements in PVM research, including their origin, classification, roles in neuroinflammation and neuroprotection, and their potential roles as therapeutic targets for neurodegenerative diseases.

The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, the parenchymal macrophages in the central nervous system (CNS), it is unclear whether brain border-associated macrophages (BAMs) also depend on this cytokine. Here, we demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34 deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function.

Microglia are the resident immune cells of the central nervous system. Unlike other glial cells-such as astrocytes and oligodendrocytes-which originate from neural stem cells alongside neurons, microglia derive from erythromyeloid progenitors that emerge in the yolk sac during early embryonic development. Once they reach the brain, microglia expand their population through proliferation during development. A growing body of research has revealed that microglia play diverse roles throughout life, both in physiological and pathological contexts. With recent advancements in single-cell transcriptomics, it has become increasingly evident that microglia exhibit substantial heterogeneity in their gene expression patterns. While various functions and subtypes of microglia are being uncovered, the mechanisms underlying their diversity remain largely unknown. Two key hypotheses may explain how microglial diversity arises. One possibility is that their diversity is influenced by the different colonization routes they take before settling in the brain. Alternatively, microglia may acquire distinct properties in response to their local environment. This review explores both possibilities, with a particular focus on the first hypothesis, drawing on recent findings that highlight the multiple routes microglia utilize to colonize the brain. It discusses how these processes contribute to the establishment of microglial diversity during brain development.

Retinal neurodegeneration leads to irreversible blindness due to the mammalian nervous system's inability to regenerate lost neurons. Efforts to regenerate retina involve two main strategies: stimulating endogenous cells to reprogram into neurons or transplanting stem-cell derived neurons into the degenerated retina. However, both approaches must overcome a major barrier in getting new neurons to grow back down the optic nerve and connect to appropriate visual targets in environments that differ significantly from developmental conditions. While immune privilege has historically been associated with the central nervous system, an emerging literature highlights the active role of immune cells in shaping neurodegeneration and regeneration. This review explores the neuroimmune interface in retinal repair, dissecting how immune interactions influence glial reprogramming, transplantation outcomes, and axonal regeneration. By integrating insights from regenerative species with mammalian models, we highlight novel immunomodulatory strategies to optimize retinal regeneration.

The brain's border tissues serve as essential hubs for neuroimmune regulation and the trafficking of biomaterials to and from the brain. These complex tissues-including the meninges, perivascular spaces, choroid plexus, and circumventricular organs-balance the brain's need for immune privilege with immune surveillance and blood-brain communication. Macrophages are integral components of these tissues, taking up key strategic positions within the brain's circulatory system. These border-associated macrophages, or "BAMs," are therefore emerging as pivotal for brain homeostasis and disease. BAMs perform trophic functions that help to support border homeostasis but also act as immune sentinels essential for border defense. In this review, we integrate recent findings on BAM origins, cell states, and functions, aiming to provide global insights and perspectives on the complex relationship between these macrophages and their border niche.

Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology.