搜索结果：Neuroimmunomodulation

PANoptosis, a collective form of programmed cell death that includes apoptosis, necroptosis, and pyroptosis, is turning out to be a key player in the neuroimmune activation and sustaining chronic neuroinflammation in the nervous system. PANoptosis, in contrast to single cell death mechanisms, is a web of events coordinating neuronal death, glial cell changes, and inflammatory signals, being implicated in the initiation and progression of neurodegenerative and neuroinflammatory diseases. This review compiles current knowledge of the molecular pathways of PANoptotic signaling, its interaction with autophagy and immune pathways, and the in vivo models utilized for its pathogenic role in the central nervous system. We also tackle translational hurdles such as biomarker identification, therapeutic safety, disease, stage precision, and patient heterogeneity, which all point to the necessity of highly accurate interventions. Moreover, novel techniques combining systems biology, AI-based target identification, and personalized neuroimmunomodulation may effectively harness PANoptosis regulation to be both controlled and disease-specific. Through bridging the gap between the mechanistic insights and the translational perspectives, this review points out that PANoptosis provides a comprehensive basis for neuroimmune-associated pathology and represents a viable target for novel therapeutic approaches to counteract both chronic neuroinflammation and neurodegeneration.

The cholinergic anti-inflammatory pathway (CAP) plays a central role in neuroimmunomodulation, and its activation is a potential strategy for ameliorating sepsis-associated acute kidney injury (SA-AKI). However, further investigations are necessary to understand the molecular mechanisms of CAP activation and develop therapies for SA-AKI. Here, we tested whether the Notch signaling pathway, which regulates cell-cell interactions, mediates the anti-inflammatory effects of CAP. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we found that CAP activation by vagus nerve stimulation (VNS) enhanced Notch2 signaling in macrophages, mitigating inflammation in the spleen and tissue damage in the kidneys. Consistently, macrophage-specific knockout of Notch2 resulted in an attenuation of these anti-inflammatory effects of VNS. We also demonstrated that VNS and macrophage-specific Notch2 signaling might upregulate transferrin, which maintains iron homeostasis, thereby protecting the kidneys. Taken together, our findings suggest the involvement of Notch signaling in the mechanisms of VNS-mediated CAP activation during LPS-induced AKI.

Recent studies increasingly support a role for autoantibodies in selected chronic pain disorders. This review examines current evidence linking autoantibodies to nociceptive sensitisation and neuroimmune dysfunction across these conditions. Experimental and clinical evidence links autoantibodies to altered neuronal excitability, neuroimmune activation, and pain hypersensitivity, particularly within the dorsal root ganglion and spinal sensory circuits. Emerging work further suggests that pathogenicity and treatment responsiveness depend on factors beyond antibody specificity alone, including tissue injury, inflammatory context, and downstream immune signalling mechanisms. Autoimmune pain disorders appear to comprise biologically heterogeneous neuroimmune syndromes in which dorsal root ganglia and anatomically connected sensory pathways emerge as recurring sites of sensitisation. Pathogenicity depends not only on antibody specificity but also on tissue context and downstream neuroimmune mechanisms, supporting the development of more targeted and mechanism-based therapeutic approaches.

Neuroinflammation is increasingly recognized as a core pathological process in various neurological diseases, including neurodegenerative disorders, stroke, autoimmune demyelinating diseases, and acute brain dysfunction associated with systemic inflammation. Among its regulatory mechanisms, the cholinergic anti-inflammatory pathway links neural activity with immune regulation. However, its neurological relevance extends beyond the classical peripheral vagus nerve-mediated inflammatory reflex. Within the central nervous system, cholinergic signaling interacts with resident immune cells, particularly microglia, and influences inflammatory tone, neuronal vulnerability, and tissue repair. Recent advances in immunometabolism further suggest that metabolic reprogramming may bridge cholinergic signaling and microglial inflammatory phenotypes. In this review, we discuss the role of cholinergic regulation of neuroinflammation from three interrelated perspectives: microglia as the hub of core cells, immune metabolism as the basis of mechanism, and neural regulation as the frontier of transformation. We first reviewed the cholinergic system and its role in neuroimmune communication, then discussed how cholinergic signals shape microglial state and metabolic process, and finally evaluated its disease-specific evidence in Alzheimer's disease, Parkinson's disease, stroke, multiple sclerosis and acute inflammatory brain dysfunction. We will also discuss pharmacological and bioelectronic methods, including targeting cholinergic receptors and vagus nerve stimulation, as emerging therapeutic strategies. By integrating cholinergic biology, microglial heterogeneity, and metabolic reprogramming, this review proposes an updated framework for understanding neuroinflammation in neurology, and highlights the future opportunities for precise neuroimmune intervention.

Oropouche virus (OROV), an emerging orthobunyavirus in the Americas, has historically been associated with self-limited febrile illness in endemic Amazon basin regions. However, recent epidemiological updates from the Pan American Health Organization (PAHO) and World Health Organization (WHO) document a marked increase in case counts and geographic expansion, with over 16,000 confirmed cases reported in 2024 and continued transmission across multiple countries in 2025, including regions where transmission had not been previously recognized. The detection of cases in the Caribbean, Central America, and imported infections in North America and Europe underscores its evolving epidemiological profile and growing global relevance. In parallel with this expansion, neurological involvement-including meningitis and encephalitis-has been reported in a subset of patients. Experimental and ex vivo studies demonstrate neural permissiveness and suggest the capacity for interaction with central nervous system (CNS) tissue. Based on established principles of viral neuroimmunology, a conservative conceptual framework is proposed linking acute neuroimmune activation during OROV infection to potential neurological manifestations. Although long-term neurological sequelae have not been systematically characterized, existing clinical observations and biological mechanisms provide plausibility for further investigation. This framework is intended to generate testable hypotheses and guide prospective studies rather than establish causality.

The cochlear aqueduct, located within the temporal bone, forms a narrow connection between the cerebrospinal fluid (CSF) in the subarachnoid space and the perilymph of the scala tympani in the inner ear. The anatomical linkage provides a potential interface for pressure regulation, molecular exchange, and therapeutic access to the cochlea. Recent findings further indicate that the cochlear aqueduct is functionally coupled to the brain's glymphatic system, permitting CSF flow to the inner ear and raising the possibility of an inner ear glymphatic system. Morphological studies demonstrate substantial interspecies variability in cochlear aqueduct size and patency among species, and identified a diaphragm-like terminal membrane at its lateral end. In mice, immunocytochemical analyses indicate a lymphatic-like phenotype reminiscent of the subarachnoid lymphatic-like membrane (SLYM). The presence of macrophages with phagocytic capacity and the fact that the membrane is activated during bacterial meningitis further supports a role in local immune surveillance. The translational relevance of the cochlear aqueduct has gained attention with advances in inner-ear gene therapy. Tracers injected in cisterna magna in mice reach the inner ear rapidly. In rodents and non-human primates, intracisternal injection of viral vectors via achieves efficient bilateral cochlear transduction, including restoration of hearing in VGLUT3-deficient mice, a model of nonsyndromic deafness. These findings position the cochlear as a minimally invasive route for inner-ear therapy, potentially avoiding direct cochlear surgery. However, interspecies differences and age-related changes in cochlear aqueduct patency must be carefully evaluated before clinical translation.

Chimeric antigen receptor-engineered cell therapies provide a novel therapeutic approach for refractory neuroimmune disorders. These cell products penetrate deep into tissue and achieve long-term depletion of pathogenic B cells and plasma cells, supporting sustained immune tolerance and durable clinical remission. Chimeric antigen receptor-T cells, chimeric antigen receptor-natural killer cells, chimeric autoantigen receptor T cells, and chimeric antigen receptor-regulatory T cells selectively target and eliminate pathological immune effectors, reduce autoantibody levels, and help maintain long-term remission in multiple sclerosis, myasthenia gravis, neuromyelitis optica spectrum disorder, chronic inflammatory demyelinating polyneuropathy, and autoimmune encephalitis. This review summarizes the therapeutic advance of chimeric antigen receptor-based cell therapies for neuroimmune disorders. Growing clinical evidence indicates that CD19-directed and B-cell maturation antigen-directed chimeric antigen receptor-T cells provide rapid and persistent clinical improvement even in patients with multiple prior treatment failures, accompanied by depletion of the B-cell lineage and sustained reduction in autoantibody titers. Key mechanisms include enhanced access across the blood-brain barrier, targeted lysis of tissue-resident memory B cells and long-lived plasma cells, and subsequent immune repertoire reconstitution. Important challenges remain incompletely defined, including long-term safety, late relapse, high manufacturing expenses, and restricted availability of autologous cell products. Further advances will require optimized chimeric antigen receptor architectures, off-the-shelf allogeneic platforms, and validation in large controlled clinical trials. This review presents a structured framework for future progress and highlights chimeric antigen receptor based immunotherapy as a pivotal strategy that replaces long term immunosuppression with durable drug free remission, thus reshaping the standard treatment model and redefining therapeutic goals for patients with neuroimmune disorders.

Neuroimmune dysregulation and altered pro- and anti-inflammatory signaling have been implicated in selected phenotypes of depressive and anxiety disorders. Interleukin-37 (IL-37), a member of the IL-1 family, exerts anti-inflammatory effects through extracellular signaling involving IL-18Rα and IL-1R8 and intracellular interactions with SMAD3. This scoping review mapped direct and indirect evidence concerning the relevance of IL-37 to depressive and anxiety disorders. PubMed/MEDLINE was searched through 12 July 2026, supplemented by backward citation searching and reference-list checking; evidence was charted by study type, population or model, IL-37 assessment, principal findings, and level of psychiatric relevance. Thirty-two IL-37-related sources were included. Direct psychiatric evidence comprised one small cross-sectional human study and two rodent stress-model studies, in which IL-37 was assessed as one component of broader inflammatory profiles rather than as a prespecified primary biomarker or intervention target. The remaining evidence was derived from non-psychiatric inflammatory conditions, central nervous system disease models, or mechanistic studies. These findings provide hypothesis-generating biological context but do not establish psychiatric specificity, causality, biomarker validity, or therapeutic efficacy. IL-37 should therefore be considered an exploratory research variable requiring validation in well-characterized longitudinal psychiatric cohorts using standardized assays and integrated immune profiling.

The regenerative repair after bone trauma is not merely an osteogenic process but a dynamic reconstruction involving the coordinated participation of multiple systems, including the nervous, immune, and vascular systems. In recent years, the regulatory role of the neuro-immune axis in bone regeneration has attracted increasing attention. Existing studies indicate that this axis may influence the quality of bone regeneration and functional recovery outcomes by modulating inflammation initiation, facilitating the transition from the inflammatory clearance phase to the reparative phase, and contributing to the remodeling of the local microenvironment. Specifically, neural signal-mediated regulation of early immune cell recruitment, macrophage polarization, and angiogenesis-osteogenesis coupling represents a critical upstream mechanism in post-traumatic bone regeneration. Conversely, an imbalance in the neuro-immune axis may be associated with adverse outcomes such as nonunion, chronic pain, and functional impairment. This article reviews the main mechanisms by which the post-traumatic neuro-immune axis regulates bone regeneration from four aspects: inflammation initiation, inflammation switching, microenvironment remodeling, and functional repair, and summarizes the research progress of related intervention strategies. Overall, targeting the neuro-immune axis may provide novel therapeutic strategies for promoting bone healing and improving functional recovery; however, most current evidence is derived from animal experiments, mechanistic studies, or early translational explorations, and its clinical value remains to be further validated.

Allergic rhinitis (AR) is traditionally defined as an IgE-mediated hypersensitivity disorder; however, this paradigm fails to explain the clinical heterogeneity observed in patients with persistent symptoms and poor therapeutic responsiveness. Emerging evidence indicates that neuro-immune interactions constitute a critical, yet underappreciated, layer of AR pathogenesis. Substance P (SP)-Mas-related G protein-coupled receptor X2 (MrgprX2) axis has recently been recognized as a central mediator of IgE-independent inflammation. Upon sensory neuron activation, SP is rapidly released and directly activates MrgprX2 on mast cells, initiating immediate inflammatory responses independent of FcεRI signaling. This pathway further drives epithelial barrier disruption and neutrophil-dominant inflammation, while sustained activation establishes neuro-immune positive feedback loops and central sensitization along the nose-brain axis, ultimately promoting chronicity and therapeutic refractoriness. Here, we integrate current evidence into a unified neuro-immune framework in which the SP-MrgprX2 axis orchestrates inflammation initiation, amplification, and maintenance beyond the classical IgE-dependent pathway. We further delineate its molecular recognition, signaling dynamics, and neuro-immune synapse organization, and discuss its crosstalk with broader inflammatory networks. On this basis, we propose mechanism-guided therapeutic strategies targeting distinct regulatory layers of this axis. Collectively, this review positions the SP-MrgprX2 axis as a key mechanistic bridge linking neural activation to chronic inflammation, advancing a neuro-immune paradigm that extends beyond IgE-mediated disease and providing a conceptual foundation for precision management of refractory AR.

Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein kinase CK2 is a holoenzyme composed of two regulatory (CK2β) and two catalytic subunits (CK2α and CK2α') and has been linked to multiple aspects of tau pathology. However, genetic evidence defining the specific contributions of CK2 subunits to tau phosphorylation and tauopathy remains lacking. Elucidating subunit-specific roles is critical for the rational development of CK2-targeted therapies. To investigate the impact of CK2 in tauopathy, Neuro-2a and primary cell cultures expressing mutant tau were treated with siRNAs targeting the two catalytic subunits of CK2, CK2α and CK2α'. In addition, the PS19 mouse model of tauopathy was bred to be haploinsufficient for the catalytic subunit CK2α'. Changes in pathology and symptomatology were analyzed via immunohistochemistry, immunoblotting, RNA-sequencing, in situ hybridization, electrophysiology, and Barnes Maze. We found that the expression of the catalytic subunit CK2α', but not catalytic CK2α or regulatory CK2β subunits, was elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using a haploinsufficient model of CK2α' in PS19 mice, we demonstrated that the PS19:CK2α'(+/-) mice had significantly decreased phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α' depletion also attenuated microglial activation, pro-inflammatory cytokine production and microglia synaptic engulfment, and enhanced synaptic gene expression, synaptic density, and long-term potentiation. Importantly, CK2α' haploinsufficiency rescued cognitive deficits assessed in the Barnes maze. Here, we show CK2α', one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α'-dependent modulation of tau phosphorylation as well as neuroinflammatory and immune signaling pathways. These findings identify CK2α' as a mechanistically defined and potentially druggable target for therapeutic strategies aimed at modifying tau-driven neurodegeneration.

Addictive drugs impact corticostriatal glutamate signaling and have immunomodulatory effects which may underlie drug-associated behaviors during different phases of the addiction cycle. Here we hypothesize that glutamate dyshomeostasis induced by addictive drug use and withdrawal is heavily orchestrated by the neuroimmune system. We systematically define how drug-induced pathologies within the nucleus accumbens (NA) glutamate tripartite synapse are tightly regulated by neuroimmune signaling. Targets within the neuroimmune system represent a novel approach that can be leveraged for clinical studies with immunomodulatory therapeutics to reverse neurobiological changes induced by addictive drugs, and thus meaningfully reduce negative clinical outcomes relevant to substance use disorders (SUDs). We outline a novel hypothesis that control of a newly defined neuroimmune-glutamate circuit and inflammasome is heavily dependent upon the type of addictive drug as well as on phase of the addiction cycle. We further provide translational evidence underscoring the tenet that neuroimmunomodulation by addictive drugs functions according to an opponent process, and we outline predictions of our opponent process hypothesis when applied to relevant polysubstance use patterns in people who use drugs. This framework could be strategically leveraged in the experimental design of clinical studies of novel SUD therapeutics.

Barrier tissues-including the skin, respiratory tract, and gastrointestinal tract-are dynamic interfaces where neural and immune systems converge to coordinate barrier defense, inflammation, and repair. Recent studies show that neurons and immune cells form bidirectional networks that sense environmental cues, pathogen-derived signals, and tissue stress to fine-tune immunity and maintain homeostasis. Sensory, sympathetic, parasympathetic, and enteric neuronal pathways shape epithelial function, vascular dynamics, and immune activation across barrier tissues. Through neurotransmitters and neuropeptides, neuroimmune circuits regulate pathogen clearance, preserve tissue integrity during infection, modulate allergic and autoimmune responses in sterile inflammation, and support tissue regeneration by instructing immune cell reprogramming and epithelial renewal. Together, these findings establish neuroimmune communication as a key regulatory layer of barrier tissue physiology and reveal therapeutic opportunities to restore immune balance and promote barrier resilience through targeted neuromodulation and immunomodulation.

The thymus is the primary lymphoid organ responsible for the generation of a self-tolerant and immunocompetent T-cell repertoire. Its function is not autonomous but is finely tuned by a complex neuroendocrine network, integrating signals from the central nervous system and the endocrine system to modulate thymopoiesis. While the roles of classical hormones and neurotransmitters in regulating thymic epithelial cell (TEC) function and T-cell development are increasingly recognized, the mechanistic pathways by which these signals are integrated within the thymic microenvironment still have much to be understood. A key, yet underexplored, component of the thymic microenvironment is the extracellular matrix (ECM). It is very clear today that ECM is not a passive scaffold but a dynamic structure that presents critical signals for thymocyte migration, proliferation, and selection. This review synthesizes current evidence to propose a novel paradigm: the thymic ECM acts as a key mediator of neuroendocrine control. We explore how specific ECM molecules, such as laminins, collagens, and fibronectin, expressed by TECs and other microenvironmental cells, can be modulated by neuroendocrine ligands. Furthermore, we discuss how these ECM modulations directly impact the presentation of key receptors, such as integrins, thereby influencing the critical crosstalk between a given thymic niche and developing lymphocytes. By delineating the ECM-mediated mechanisms, this review aims to provide a more holistic understanding of how neuroendocrine factors govern thymic physiology, with implications for aging, stress-related immunosenescence, and therapeutic strategies aimed at thymic regeneration.

Interleukin-33 (IL-33), an alarmin cytokine of the IL-1 family, has emerged as a pivotal regulator of neuroimmune interactions in the central nervous system (CNS). Acting through its receptor ST2, IL-33 orchestrates diverse immune responses by modulating microglial polarization, shaping T cell differentiation, activating type 2 innate lymphoid cells (ILC2s), and engaging mast cell-macrophage regulatory circuits. Across distinct neurological disorders, including epilepsy, stroke, traumatic brain injury (TBI), Parkinson's disease (PD), Alzheimer's disease (AD), multiple sclerosis (MS), cerebral malaria, and glioma, IL-33 exerts both protective and pathogenic effects in a context-dependent manner. In epilepsy, IL-33 modulates neuroinflammation and neuronal excitability; in stroke, it attenuates acute neurovascular injury while influencing post-stroke remodeling; in AD, it enhances amyloid-β clearance and mitigates chronic neuroinflammation; in MS, it regulates autoimmune demyelination via T cell and innate immune pathways. These shared yet disease-specific mechanisms underscore IL-33's central role in neuroimmune homeostasis and its potential as a precision therapeutic target. Future research integrating multi-disease models, temporal disease staging, and single-cell multi-omics will be essential to define the conditions under which IL-33 modulation yields maximal therapeutic benefit.

The effects of adjuvant hyperthermia on glioblastoma-associated astrocytes remain poorly characterized. This study aimed to investigate the role of the purinergic P2X7 receptor, an ATP-gated ion channel, in mediating heat-induced astrocyte activation and its impact on tumor progression. Primary mouse astrocytes were subjected to heat stress (mild hyperthermia at 42°C). P2X7 signaling was examined using a specific antagonist (A-740003), siRNA-mediated knockdown, and live-cell calcium imaging. Astrocyte activation was evaluated by assessing Glial Fibrillary Acidic Protein (GFAP) expression and pro-inflammatory markers. The pro-tumorigenic potential of astrocyte-conditioned medium was tested on U87 glioblastoma cells. An orthotopic mouse model was used to validate the effects of local hyperthermia, with or without P2X7 inhibition. Mild hyperthermia upregulated P2X7 expression in astrocytes and induced a substantial calcium influx, leading to activation of the Calcineurin-NFAT pathway. This process promoted a reactive astrocyte phenotype and a pro-tumorigenic secretory profile, enhancing U87 cell proliferation, migration, and invasion. In vivo, mild hyperthermia was associated with increased tumor progression, which was attenuated by pharmacological inhibition of P2X7. Heat stress facilitates glioblastoma progression by activating astrocytes through the P2X7-mediated calcium-calcineurin-NFAT signaling pathway. These findings highlight P2X7 as a potential therapeutic target for optimizing hyperthermia-based strategies in glioblastoma treatment.

Perioperative neurocognitive disorders (PND) are common and highly heterogeneous neurological complications in older and otherwise vulnerable surgical patients, with clinical manifestations ranging from delayed cognitive recovery to persistent postoperative cognitive decline. Although neuroinflammation is closely associated with the development of PND, an integrative framework is still lacking to explain how perioperative systemic immune activation leads to sustained central immune imbalance and cognitive dysfunction. Here, we propose that the brain immune landscape is a key determinant of susceptibility to PND. This landscape represents a baseline phenotype defined by central immune cell states, inflammatory activation thresholds, and resolution capacity. Within this microglia-centered framework, multiple perioperative factors may jointly drive maladaptive transitions in microglial states. We further discuss mitochondrial stress, glycolytic bias, epigenetic remodeling, non-coding RNA regulation, and trained immunity-like mechanisms, suggesting that these processes may serve as important drivers of sustained neuroimmune imbalance. This perspective supports time- and state-dependent, biomarker-guided intervention strategies aimed at preserving inflammatory resolution and enhancing perioperative cognitive resilience.

Excessive intake of saturated fats triggers inflammation in the hypothalamus, a key regulator of energy balance. In the chronic phase of this inflammatory response, bone marrow-derived and lymphoid cells are chemoattracted to this region, partially mitigating high-fat diet (HFD)-induced metabolic impairments. In rodents, the onset and magnitude of this inflammation differ between males and females, reflecting sex-specific patterns of metabolic regulation. However, how the hypothalamic chemokine profile evolves during HFD-induced inflammation, and whether it is influenced by biological sex, remains unclear. Here, male and female C57BL/6J mice were fed a HFD for 1, 3, 14, or 28 days. To isolate the role of ovarian hormones in modulating hypothalamic chemokine profile, we also analyzed ovariectomized (OVX) females with or without estrogen replacement. Quantitative polymerase chain reaction-based expression analysis revealed that most chemokines and their receptors were transiently modulated in the hypothalamus during the course of the HFD exposure, showing reduced levels in the acute phase and normalization during the chronic phase. Despite the modest sex-dependent effects observed, messenger RNA expression of the chemokine receptor C-X-C motif chemokine receptor 3 (CXCR3) was significantly higher in females than in males after 14 and 28 days of HFD, suggesting faster recruitment of CXCR3+ immune cells that may contribute to female protection against metabolic dysfunction. Females lacking ovarian hormone production displayed increased hypothalamic expression of Cxcr3 and Ccl2. Only Cxcr3 expression was partially normalized by estradiol treatment, suggesting that non-estrogenic ovarian factors may play a role in modulating specific chemokine signaling pathways. Together, our findings show that hypothalamic chemokine signaling is dynamically and transiently regulated throughout the phases of HFD-induced inflammation, with Cxcr3 modulation by HFD and ovarian hormones contributing to sex-specific resilience against metabolic inflammation.

Background the deployment of fifth-generation (5G) wireless telecommunications infrastructure, incorporating millimeter-wave (mmWave, 24-100 GHz) and sub-6 GHz frequencies, has renewed scientific and public health interest in the potential neurobiological effects of radiofrequency electromagnetic fields (RF-EMF). While extensive research has examined lower-frequency RF-EMF from 2G/3G/4G technologies, the specific effects of mmWave frequencies on CNS cellular biology-including microglial polarization and intracellular calcium signaling-remain less characterized. This systematic review evaluates experimental evidence from in vitro and in vivo studies on the effects of high-frequency EMF (300 MHz-300 GHz) on neuroimmune responses, microglial function, CNS calcium homeostasis, and related outcomes. Methods PubMed, EMBASE, Web of Science, and the EMF-Portal were searched from inception to January 2026 following PRISMA 2020 guidelines. Experimental (in vitro and animal) studies reporting CNS-relevant outcomes after high-frequency RF-EMF exposure were eligible. Exposure must have been within the 300 MHz to 300 GHz range. Quality assessment used adapted OHAT risk-of-bias criteria. A narrative synthesis was conducted; quantitative pooling was performed where three or more studies reported the same outcome. Results forty-one studies met inclusion criteria (see PRISMA Flow Diagram, Fig. 1): 7 in vitro (cell culture), 29 in vivo (rodent model), and 5 reviews/meta-analyses. The detailed characteristics of all included studies are summarized in Table 1. At specific absorption rate (SAR) levels at or below the International Commission on Non-Ionizing Radiation Protection (ICNIRP) general public exposure guidelines (2 W/kg averaged over 10 g), the majority of studies (27/41, 66%) found no statistically significant effects on neuroinflammatory markers, microglial morphology, or calcium signaling. Eleven studies (27%) reported transient, low-magnitude increases in intracellular Ca²⁺ or pro-inflammatory cytokine expression at exposures near or exceeding guideline limits; these effects were not consistently reproducible across independent laboratories. Three studies (7%) reported effects below guideline thresholds that may warrant further investigation. No study identified neuropathological changes (neuronal death, axonal injury) attributable to RF-EMF at guideline-compliant exposures. Conclusions current experimental evidence does not establish that high-frequency RF-EMF at guideline-compliant exposure levels produces significant adverse effects on microglial polarization, CNS calcium homeostasis, or neuroinflammatory responses. Methodological heterogeneity, inadequate dosimetry, and limited independent replication constrain confidence in both positive and negative findings. Standardized, rigorously controlled experimental studies are needed, particularly for mmWave frequencies (> 6 GHz) where data are sparse. Our findings support the current scientific consensus that high-frequency RF-EMF below regulatory limits does not pose a clearly established neurobiological hazard. The rollout of 5G wireless networks uses higher radio frequencies than previous mobile technologies, including millimeter waves that have never been widely used in telecommunications before. Some members of the public are concerned that these frequencies might harm the brain. This review examined published laboratory studies in which cells or animals were exposed to these high-frequency radio waves to see whether they affected brain immune cells (called microglia) or the calcium levels inside brain cells. We found 41 studies, most of which showed no significant effects at the exposure levels allowed by safety guidelines. A minority of studies found small, temporary changes in cellular calcium or inflammation markers, mostly at higher exposures above regulatory limits. No study found evidence of actual brain cell damage from compliant exposures. The current evidence does not establish that these radio frequencies are harmful to the brain at the levels people encounter in everyday life. However, millimeter-wave frequencies have been less studied than older technologies, and more rigorous, standardized experiments are needed to fully characterise their biological effects before next-generation telecommunications infrastructure is widely deployed.