Astrocytic Regulation Research Articles

Aging-Related Changes in Expression and Function of Glutamate Transporters in Rat Spinal Cord Astrocytes

Astrocytes make up the predominant cell population among glial cells in the mammalian brain, and they play a vital role in ensuring its optimal functioning. They promote neuronal health and survival and protect neurons from glutamate-induced excitotoxicity. In the spinal cord’s dorsal horn (DH) and ventral horn (VH) regions, astrocytes serve crucial roles. Notably, VH motor neurons exhibit a heightened sensitivity to glutamate-induced damage. It is posited that this selective sensitivity could be related to their localized presence within the VH, where astrocytes possess a distinct set of mechanisms for managing glutamate. As organisms age, the risk of damage from glutamate increases, indicating a potential decline in the efficiency of astrocytic glutamate regulation. Our research involved an analysis of astrocytic structure, glutamate transporter levels, and glutamate uptake capabilities within the DH and VH through immunohistochemical methods, protein analysis via Western blot, and patch-clamp studies in electrophysiology. The investigations revealed a decrease in both the number and coverage of astroglia in the spinal cord, more so within the VH as aging progressed. Notably, levels of the excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2) also decreased with age, particularly within the VH. Patch-clamp analyses of astrocytes from both spinal regions confirmed a significant reduction in glutamate uptake activity as age advanced, indicating an age-related impairment in glutamate processing. The findings indicate aging leads to distinct changes in DH and VH astrocytes, impairing their glutamate management abilities, which could contribute significantly to the development of late-onset neurodegenerative conditions.

Regulation of NAD+/NADH Redox Involves the Protective Effects of Ginsenoside Rb1 against Oxygen-Glucose Deprivation/Reoxygenation-Induced Astrocyte Lesions.

The aim of this study was to investigate NAD+/NADH redox regulation in astrocytes by Ginsenoside Rb1 subjected to oxygen-glucose deprivation/reoxygenation (OGD/R) and to reveal the neuroprotective mechanism of ginseng. Neonatal mouse brain was used to culture primary astrocytes. The third generation of the primary astrocytes was used for the experiments. OGD/R was introduced by culturing the cells in a glucose-free media under nitrogen for 6 h followed by a regular culture for 24 h. Ginsenoside Rb1 attenuated OGD/R-induced astrocyte injury in a dose-dependent manner. It improved the mitochondrial function of OGD/R astrocytes indicated by improving mitochondrial distribution, increasing mitochondrial membrane potential, and enhancing mitochondrial DNA copies and ATP production. Ginsenoside Rb1 significantly lifted intracellular NAD+/NADH, NADPH/NADP+, and GSH/GSSG in OGD/R astrocytes. It inhibited the protein expression of both PARP1 and CD38, while attenuating the SIRT1 drop in OGD/R cells. In line with its effects on PARP1, Ginsenoside Rb1 significantly reduced the expression of poly-ADP-ribosylation (PARylation) proteins in OGD/R cells. Ginsenoside Rb1 also significantly increased the expression of NAMPT and NMNAT2, both of which are key players in NAD/NADH synthesis. The results suggest that the regulation of NAD+/NADH redox involves the protective effects of ginsenoside Rb1 against OGD/R-induced astrocyte injury.

Brain fog in long COVID: A glutamatergic hypothesis with astrocyte dysfunction accounting for brain PET glucose hypometabolism

Brain [18F]FDG-PET scans have revealed a glucose hypometabolic pattern in patients with long COVID. This hypometabolism might reflect primary astrocyte dysfunction. Astrocytes play a key role in regulating energy metabolism to support neuronal and synaptic activity, especially activity involving glutamate as the main neurotransmitter. Neuroinflammation is one of the purported mechanisms to explain brain damage caused by infection with SARS-CoV-2. Microglial activation can trigger reactive astrogliosis, contributing to neuroinflammatory changes. These changes can disturb glutamatergic homeostasis, ultimately leading to cognitive fatigue, which has been described in other clinical situations. We hypothesize that glutamatergic dysregulation related to astrocyte dysfunction could be the substrate of brain PET hypometabolism in long COVID patients with brain fog. Based on these elements, we propose that therapeutics targeting astrocytic glutamate regulation could help mitigate long COVID neurological manifestations.

Astrocytic transcription factors REST, YY1, and putative microRNAs in Parkinson’s disease and advanced therapeutic strategies

Transcription factors (TF) and microRNAs are regulatory factors in astrocytes and are linked to several Parkinson’s disease (PD) progression causes, such as disruption of glutamine transporters in astrocytes and concomitant disrupted glutamine uptake and inflammation. REST, a crucial TF, has been documented as an epigenetic repressor that limits the expression of neuronal genes in non-neural cells. REST activity is significantly linked to its corepressors in astrocytes, specifically histone deacetylases (HDACs), CoREST, and MECP2. Another REST-regulating TF, YY1, has been studied in astrocytes, and its interaction with REST has been investigated. In this review, the molecular processes that support the astrocytic control of REST and YY1 in terms of the regulation of glutamate transporter EAAT2 were addressed in a more detailed and comprehensive manner. Both TFs' function in astrocytes and how astrocyte abnormalities cause PD is still a mystery. Moreover, microRNAs (short non-coding RNAs) are key regulators that have been correlated to the expression and regulation of numerous genes linked to PD. The identification of numerous miRs that are engaged in astrocyte dysfunction that triggers PD has been shown. The term “Gut-brain axis” refers to the two systems' mutual communication. Gut microbial dysbiosis, which mediates an imbalance of the gut-brain axis, might contribute to neurodegenerative illnesses through altered astrocytic regulation. New treatment approaches to modify the gut-brain axis and prevent astrocytic repercussions have also been investigated in this review.

Astromorphic Self-Repair of Neuromorphic Hardware Systems

While neuromorphic computing architectures based on Spiking Neural Networks (SNNs) are increasingly gaining interest as a pathway toward bio-plausible machine learning, attention is still focused on computational units like the neuron and synapse. Shifting from this neuro-synaptic perspective, this paper attempts to explore the self-repair role of glial cells, in particular, astrocytes. The work investigates stronger correlations with astrocyte computational neuroscience models to develop macro-models with a higher degree of bio-fidelity that accurately captures the dynamic behavior of the self-repair process. Hardware-software co-design analysis reveals that bio-morphic astrocytic regulation has the potential to self-repair hardware realistic faults in neuromorphic hardware systems with significantly better accuracy and repair convergence for unsupervised learning tasks on the MNIST and F-MNIST datasets. Our implementation source code and trained models are available at https://github.com/NeuroCompLab-psu/Astromorphic_Self_Repair.

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation.

Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.

Astrocyte Regulation of Stress- and Ethanol Dependence-Induced Changes in Reward Seeking

Astrocyte Regulation of Stress- and Ethanol Dependence-Induced Changes in Reward Seeking

G protein‐biased GPR3 signaling induces glial activation and ameliorates amyloid pathology in a preclinical Alzheimer’s disease mouse model

AbstractBackgroundBiased G protein‐coupled receptor (GPCR) ligands preferentially activate G protein‐ or β‐arrestin signaling pathways and are leading to the development of drugs with superior efficacy and reduced side‐effects in heart disease, pain management, and neuropsychiatric disorders. Although GPCRs are implicated in the pathophysiology of Alzheimer’s disease (AD), biased GPCR signaling is an unexplored area of investigation in AD. Previous work demonstrated that Gpr3 deficiency ameliorates amyloid‐β (Aβ) pathology. However, Gpr3‐deficient mice display several adverse phenotypes, including elevated anxiety‐like behavior, reduced fertility, and memory impairment, which are potentially associated with impaired G protein‐signaling. We hypothesized that generation of a G protein‐biased GPR3 mouse model, which maintains G protein‐signaling while eliminating β‐arrestin signaling, would attenuate AD‐associated phenotypes while preserving the beneficial effects of GPR3‐mediated G protein‐signaling.MethodsWe used a CRISPR/Cas9 genome‐editing strategy to develop two novel G protein‐biased GPR3 mouse models. We utilized a broad range of molecular, cellular, and biochemical methodologies, including mass spectrometry, immunoblot and immunohistochemical analyses, RNA profiling, and behavioral testing to determine the physiological relevance of G protein‐biased GPR3 signaling in naïve mice and in the preclinical AppNL‐G‐F AD mouse model.ResultsWe determine that, in contrast to Gpr3‐deficient mice, G protein‐biased GPR3 mice do not display elevated anxiety levels, reduced fertility, or cognitive impairment. We then established that GPR3 is expressed in neurons, microglia, and astrocytes and is associated with cell‐type‐specific effects on AD pathogenesis. Accordingly, we determine that G protein‐biased signaling leads to a reduction in Aβ generation in neurons, the activation and hypertrophy of disease‐associated‐microglia (DAM) and pan‐reactive astrocytes, and to an increase in amyloid plaque compaction in AppNL‐G‐F mice.ConclusionsThese studies provide the first demonstration of G protein‐biased signaling in neuronal regulation of Aβ generation and microglial and astrocytic regulation of neuroinflammation in a preclinical AD mouse model and open an exciting area of investigation on biased agonism as a therapeutic intervention strategy for AD.

Inhibition of lysophosphatidic acid receptor 1 relieves PMN recruitment in CNS via LPA1/TSP1/CXCR2 pathway and alleviates disruption on blood-brain barrier following intracerebral haemorrhage in mice

BackgroudThe frequencies of morbidity and impairment associated with spontaneous intracerebral haemorrhage (ICH) are comparatively high. Blood-brain barrier (BBB) integrity was compromised due to subsequent brain injury induced by ICH, which is crucial for a poor prognosis. Polymorphonuclear leukocyte (PMN) strongly modulate the disruption of BBB in the central nervous system (CNS). The lysophosphatidic acid receptor 1 (LPA1) mediated thrombospondin-1 (TSP1) regulation in astrocytes, which induce macrophage inflammatory protein 2(MIP2) secretion. MIP2 enhance PMN recruitment through CXC chemokine type 2 (CXCR2) activation. The purpose of this study was to investigate whether the LPA1-mediated inhibition of PMN recruitment and BBB protection after ICH is regulated by TSP1 and CXCR2 networks.MethodsICH induction was performed in CD1 mice using collagenase administration. AM966, a targeted LPA1 antagonist, was orally administered 1 and 12 h following ICH. further identify possible LPA1-mediated BBB protection mechanisms, we intracerebroventricularly (ICV) administered a CXCR2 ligand MIP2, as well as TSP1 CRISPR activation (ACT) with AM966. Consequently, we performed neurobehavioral, brain water content (BWC), Evans blue staining (EBS), immunofluorescence (IF), and western blot (WB) analyses.ResultsAfter ICH, astrocytes showed signs of LPA1, which peaked after 24 h, while PMN\\ displayed evidence of CXCR2. The AM966-mediated LPA1 suppression relieved PMN recruitment, diminished brain oedema, demonstrated extravasation (as evidenced by EBS), protected BBB integrity, and enhanced neurologic activity following ICH. AM966 treatment strongly reduced TSP1, CXCR2, Occludin, and Claudin-5 expressions and PMN recruitment following ICH, and their expressions were restored by MIP2 and TSP1 CRISPR (ACT).ConclusionsThis study shows that LAP1 suppression reduced PMN recruitment after ICH in mice via TSP1/CXCR2 signalling, which minimized BBB disruption and improved the CNS’s neurobehavioral functioning. Hence, LPA1 is a strong candidate for therapy to reduce PMN recruitment and offer protection of BBB integrity after ICH.

Information Encoding in Bursting Spiking Neural Network Modulated by Astrocytes.

We investigated a mathematical model composed of a spiking neural network (SNN) interacting with astrocytes. We analysed how information content in the form of two-dimensional images can be represented by an SNN in the form of a spatiotemporal spiking pattern. The SNN includes excitatory and inhibitory neurons in some proportion, sustaining the excitation-inhibition balance of autonomous firing. The astrocytes accompanying each excitatory synapse provide a slow modulation of synaptic transmission strength. An information image was uploaded to the network in the form of excitatory stimulation pulses distributed in time reproducing the shape of the image. We found that astrocytic modulation prevented stimulation-induced SNN hyperexcitation and non-periodic bursting activity. Such homeostatic astrocytic regulation of neuronal activity makes it possible to restore the image supplied during stimulation and lost in the raster diagram of neuronal activity due to non-periodic neuronal firing. At a biological point, our model shows that astrocytes can act as an additional adaptive mechanism for regulating neural activity, which is crucial for sensory cortical representations.

A tribute to Leif Hertz: The historical context of his pioneering studies of the roles of astrocytes in brain energy metabolism, neurotransmission, cognitive functions, and pharmacology identifies important, unresolved topics for future studies.

Leif Hertz, M.D., D.Sc. (honōris causā) (1930-2018), was one of the original and noteworthy participants in the International Conference on Brain Energy Metabolism (ICBEM) series since its inception in 1993. The biennial ICBEM conferences are organized by neuroscientists interested in energetics and metabolism underlying neural functions; they have had a high impact on conceptual and experimental advances in these fields and on promoting collaborative interactions among neuroscientists. Leif made major contributions to ICBEM discussions and understanding of metabolic and signaling characteristics of astrocytes and their roles in brain function. His studies ranged from uptake of K+ from extracellular fluid and its stimulation of astrocytic respiration, identification, and regulation of enzymes specifically or preferentially expressed in astrocytes in the glutamate-glutamine cycle of excitatory neurotransmission, a requirement for astrocytic glycogenolysis for fueling K+ uptake, involvement of glycogen in memory consolidation in the chick, and pharmacology of astrocytes. This tribute to Leif Hertz highlights his major discoveries, the high impact of his work on astrocyte-neuron interactions, and his unparalleled influence on understanding the cellular basis of brain energy metabolism. His work over six decades has helped integrate the roles of astrocytes into neurotransmission where oxidative and glycogenolytic metabolism during neurotransmitter glutamate turnover are key aspects of astrocytic energetics. Leif recognized that brain astrocytic metabolism is greatly underestimated unless the volume fraction of astrocytes is taken into account. Adjustment for pathway rates expressed per gram tissue for volume fraction indicates that astrocytes have much higher oxidative rates than neurons and astrocytic glycogen concentrations and glycogenolytic rates during sensory stimulation in vivo are similar to those in resting and exercising muscle, respectively. These novel insights are typical of Leif's astute contributions to the energy metabolism field, and his publications have identified unresolved topics that provide the neuroscience community with challenges and opportunities for future research.

Possible Effects of Acupuncture in Poststroke Aphasia.

Neural plasticity promotes the reorganization of language networks and is an essential recovery mechanism for poststroke aphasia (PSA). Neuroplasticity may be a pivotal bridge to elucidate the potential recovery mechanisms of acupuncture for aphasia. Therefore, understanding the neuroplasticity mechanism of acupuncture in PSA is crucial. However, the underlying therapeutic mechanism of neuroplasticity in PSA after acupuncture needs to be explored. Excitotoxicity after brain injury affects the activity of neurotransmitters and disrupts the transmission of normal neuron information. Thus, a helpful strategy of acupuncture might be to improve PSA by affecting the availability of these neurotransmitters and glutamate receptors at synapses. In addition, the regulation of neuroplasticity by acupuncture may also be related to the regulation of astrocytes. Considering the guiding significance of acupuncture for clinical treatment, it is necessary to carry out further study about the influence of acupuncture on the recovery of aphasia after stroke. This study summarizes the current research on the neural mechanism of acupuncture in treating PSA. It seeks to elucidate the potential effect of acupuncture on the recovery of PSA from the perspective of synaptic plasticity and integrity of gray and white matter.

Astrocytes mediate cell non-autonomous correction of aberrant firing in human FXS neurons

Pre-clinical studies of fragile X syndrome (FXS) have focused on neurons, with the role of glia remaining largely underexplored. We examined the astrocytic regulation of aberrant firing of FXS neurons derived from human pluripotent stem cells. Human FXS cortical neurons, co-cultured with human FXS astrocytes, fired frequent short-duration spontaneous bursts of action potentials compared with less frequent, longer-duration bursts of control neurons co-cultured with control astrocytes. Intriguingly, bursts fired by FXS neurons co-cultured with control astrocytes are indistinguishable from control neurons. Conversely, control neurons exhibit aberrant firing in the presence of FXS astrocytes. Thus, the astrocyte genotype determines the neuronal firing phenotype. Strikingly, astrocytic-conditioned medium, and not the physical presence of astrocytes, is capable of determining the firing phenotype. The mechanistic basis of this effect indicates that the astroglial-derived protein, S100β, restores normal firing by reversing the suppression of a persistent sodium current in FXS neurons.

The Role of Glutamate Receptors in Epilepsy

Glutamate is an essential excitatory neurotransmitter in the central nervous system, playing an indispensable role in neuronal development and memory formation. The dysregulation of glutamate receptors and the glutamatergic system is involved in numerous neurological and psychiatric disorders, especially epilepsy. There are two main classes of glutamate receptor, namely ionotropic and metabotropic (mGluRs) receptors. The former stimulate fast excitatory neurotransmission, are N-methyl-d-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), and kainate; while the latter are G-protein-coupled receptors that mediate glutamatergic activity via intracellular messenger systems. Glutamate, glutamate receptors, and regulation of astrocytes are significantly involved in the pathogenesis of acute seizure and chronic epilepsy. Some glutamate receptor antagonists have been shown to be effective for the treatment of epilepsy, and research and clinical trials are ongoing.

Gastrocytes and GLUttony - astrocyte regulation of calorie intake via glutamatergic modulation of gastric activity in rats.

Gastrocytes and GLUttony - astrocyte regulation of calorie intake via glutamatergic modulation of gastric activity in rats.

Brainstem astrocytes control homeostatic regulation of caloric intake.

Prolonged high-fat diet (HFD) exposure is associated with hyperphagia, excess caloric intake and weight gain. After initial exposure to a HFD, a brief (24-48h) period of hyperphagia is followed by the regulation of caloric intake and restoration of energy balance within an acute (3-5day) period. Previous studies have demonstrated this occurs via a vagally mediated signalling cascade that increases glutamatergic transmission via activation of NMDA receptors located on gastric-projecting neurons of the dorsal motor nucleus of the vagus (DMV). The present study used electrophysiological recordings from thin brainstem slice preparations, in vivo recordings of gastric motility and tone, measurement of gastric emptying rates, and food intake studies to investigate the hypothesis that activation of brainstem astrocytes in response to acute HFD exposure is responsible for the increased glutamatergic drive to DMV neurons and the restoration of caloric balance. Pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV excitability, dysregulated gastric tone and motility, attenuated the homeostatic delay in gastric emptying, and prevented the decrease in food intake that is observed during the period of energy regulation following initial exposure to HFD. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome. KEY POINTS: Initial exposure to a high fat diet is associated with a brief period of hyperphagia before caloric intake and energy balance is restored. This period of homeostatic regulation is associated with a vagally mediated signalling cascade that increases glutamatergic transmission to dorsal motor nucleus of the vagus (DMV) neurons via activation of synaptic NMDA receptors. The present study demonstrates that pharmacological and chemogenetic inhibition of brainstem astrocytes reduced glutamatergic signalling and DMV neuronal excitability, dysregulated gastric motility and tone and emptying, and prevented the regulation of food intake following high-fat diet exposure. Astrocyte regulation of glutamatergic transmission to DMV neurons appears to involve release of the gliotransmitters glutamate and ATP. Understanding the mechanisms involved in caloric regulation may provide critical insights into energy balance as well as into the hyperphagia that develops as these mechanisms are overcome.

MicroRNA-mediated regulation of reactive astrocytes in central nervous system diseases.

Astrocytes (AST) are abundant glial cells in the human brain, accounting for approximately 20-50% percent of mammalian central nervous system (CNS) cells. They display essential functions necessary to sustain the physiological processes of the CNS, including maintaining neuronal structure, forming the blood-brain barrier, coordinating neuronal metabolism, maintaining the extracellular environment, regulating cerebral blood flow, stabilizing intercellular communication, participating in neurotransmitter synthesis, and defending against oxidative stress et al. During the pathological development of brain tumors, stroke, spinal cord injury (SCI), neurodegenerative diseases, and other neurological disorders, astrocytes undergo a series of highly heterogeneous changes, which are called reactive astrocytes, and mediate the corresponding pathophysiological process. However, the pathophysiological mechanisms of reactive astrocytes and their therapeutic relevance remain unclear. The microRNAs (miRNAs) are essential for cell differentiation, proliferation, and survival, which play a crucial role in the pathophysiological development of CNS diseases. In this review, we summarize the regulatory mechanism of miRNAs on reactive astrocytes in CNS diseases, which might provide a theoretical basis for the diagnosis and treatment of CNS diseases.

Cyclic AMP response element-binding protein (CREB) transcription factor in astrocytic synaptic communication.

Astrocytes are known to actively participate in synaptic communication by forming structures called tripartite synapses. These synapses consist of presynaptic axon terminals, postsynaptic dendritic spines, and astrocytic processes where astrocytes release and receive transmitters. Although the transcription factor cyclic AMP response element (CRE)-binding protein (CREB) has been actively studied as an important factor for mediating synaptic activity-induced responses in neurons, its role in astrocytes is relatively unknown. Synaptic signals are known to activate various downstream pathways in astrocytes, which can activate the CREB transcription factor. Therefore, there is a need to summarize studies on astrocytic intracellular pathways that are induced by synaptic communication resulting in activation of the CREB pathway. In this review, we discuss the various neurotransmitter receptors and intracellular pathways that can induce CREB activation and CREB-induced gene regulation in astrocytes.

Identification of astrocyte regulators by nucleic acid cytometry.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system1. Astrocytes are heterogeneous glial cells that are resident in the central nervous system and participate in the pathogenesis of multiple sclerosis and its model experimental autoimmune encephalomyelitis2,3. However, few unique surface markers are available for the isolation of astrocyte subsets, preventing their analysis and the identification of candidate therapeutic targets; these limitations are further amplified by the rarity of pathogenic astrocytes. Here, to address these challenges, we developed focused interrogation of cells by nucleic acid detection and sequencing (FIND-seq), a high-throughput microfluidic cytometry method that combines encapsulation of cells in droplets, PCR-based detection of target nucleic acids and droplet sorting to enable in-depth transcriptomic analyses of cells of interest at single-cell resolution. We applied FIND-seq to study the regulation of astrocytes characterized by the splicing-driven activation of the transcription factor XBP1, which promotes disease pathology in multiple sclerosis and experimental autoimmune encephalomyelitis4. Using FIND-seq in combination with conditional-knockout mice, in vivo CRISPR-Cas9-driven genetic perturbation studies and bulk and single-cell RNAsequencing analyses of samples frommouse experimental autoimmune encephalomyelitis and humans with multiple sclerosis, we identified a new role for the nuclear receptor NR3C2 and its corepressor NCOR2 in limiting XBP1-driven pathogenic astrocyte responses. In summary, we used FIND-seq to identify a therapeutically targetable mechanism that limits XBP1-driven pathogenic astrocyte responses. FIND-seq enables the investigation of previously inaccessible cells, including rare cell subsets defined by unique gene expression signatures or other nucleic acid markers.

Mesenchymal Stem Cells-based Cell-free Therapy Targeting Neuroinflammation.

Emerging from several decades of extensive research, key genetic elements and biochemical mechanisms implicated in neuroinflammation have been delineated, contributing substantially to our understanding of neurodegenerative diseases (NDDs). In this minireview, we discuss data predominantly from the past three years, highlighting the pivotal roles and mechanisms of the two principal cell types implicated in neuroinflammation. The review also underscores the extended process of peripheral inflammation that predates symptomatic onset, the critical influence of neuroinflammation, and their dynamic interplay in the pathogenesis of NDDs. Confronting these complex challenges, we introduce compelling evidence supporting the use of mesenchymal stem cell-based cell-free therapy. This therapeutic strategy includes the regulation of microglia and astrocytes, modulation of peripheral nerve cell inflammation, and targeted anti-inflammatory interventions specifically designed for NDDs, while also discussing engineering and safety considerations. This innovative therapeutic approach intricately modulates the immune system across the peripheral and nervous systems, with an emphasis on achieving superior penetration and targeted delivery. The insights offered by this review have significant implications for the better understanding and management of neuroinflammation.