Journal of Neuroinflammation最新文献

Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Background: Congenital cytomegalovirus (CMV) infections represent one leading cause of human neurodevelopmental disorders. Despite their high prevalence and severity, no satisfactory therapy is available and pathophysiology remains elusive. The pathogenic involvement of immune processes occurring in infected developing brains has been increasingly documented. Here, we have used our previously validated rat model of CMV infection of the fetal brain in utero to test whether the maternal administration of four different drugs with immunomodulatory properties would have an impact on the detrimental postnatal outcome of CMV infection.

Methods: CMV infection of the rat fetal brain was done intracerebroventricularly. Each of the drugs, including acetylsalicylic acid (aspirin, ASA), a classical inhibitor of cyclooxygenases Cox-1 and Cox-2, the two key rate-limiting enzymes of the arachidonic acid-to-prostaglandins (PG) synthesis pathway, was administered to pregnant dams until delivery. ASA was selected for subsequent analyses based on the improvement in postnatal survival. A combination of qRT-PCR, mass spectrometry-based targeted lipidomics, immunohistochemistry experiments, monitoring of neurologic phenotypes and electrophysiological recordings was used to assess the impact of ASA in CMV-infected samples and pups. The postnatal consequences of CMV infection were also analyzed in rats knocked-out (KO) for Cox-1.

Results: Increased PGE2 levels and increased proportions of Cox-1⁺ and Cox-2⁺ microglia were detected in CMV-infected developing brains. Maternal intake of ASA led to decreased proportion of Cox-1⁺ fetal, but not neonatal, microglia, while leaving the proportions of Cox-2⁺ microglia unchanged. Maternal intake of ASA also improved the key postnatal in vivo phenotypes caused by CMV infection and dramatically prevented against the spontaneous epileptiform activity recorded in neocortical slices from CMV-infected pups. In contrast with maternal intake of ASA, Cox-1 KO pups displayed no improvement in the in vivo phenotypes after CMV infection. However, as with ASA administration, the spontaneous epileptiform activity was dramatically inhibited in neocortical slices from CMV-infected, Cox-1 KO pups.

Conclusion: Overall, our data indicate that, in the context of CMV infection of the fetal brain, maternal intake of ASA during pregnancy improved CMV-related neurodevelopmental alterations in the offspring, likely via both Cox-1 dependent and Cox-1 independent mechanisms, and provide proof-of-principle for the use of ASA against the detrimental outcomes of congenital CMV infections.

Recent advances in neuroscience have transformed our understanding of the meninges, the layers surrounding the central nervous system (CNS). Two key findings have advanced our understanding: researchers identified cranial bone marrow as a reservoir for meningeal immune cells, and rediscovered a brain lymphatic system. Once viewed merely as a protective barrier, the meninges are now recognized as a dynamic interface crucial for neuroimmune interactions. This shift in perspective highlights their unique role in maintaining CNS balance, shaping brain development, and regulating responses to injury and disease. This review synthesizes the latest insights into meningeal anatomy and function, with a focus on newly identified structures such as dural-associated lymphoid tissues (DALT) and arachnoid cuff exit (ACE) points. We also examine the diverse immune cell populations within the meninges and their interactions with the CNS, underscoring the emerging view of the meninges as active participants in brain immunity. Finally, we outline critical unanswered questions about meningeal immunity, proposing directions for future research. By addressing these knowledge gaps, we aim to deepen our understanding of the meninges' role in brain health and disease, potentially paving the way for novel therapeutic approaches.

Background: Research on traumatic brain injury (TBI) highlights the significance of counteracting its metabolic impact via exogenous fuels to support metabolism and diminish cellular damage. While ethyl pyruvate (EP) treatment shows promise in normalizing cellular metabolism and providing neuroprotection, there is a gap in understanding the precise metabolic pathways involved. Metabolomic analysis of the acute post-injury metabolic effects, with and without EP treatment, aims to deepen our knowledge by identifying and comparing the metabolite profiles, thereby illuminating the injury's effects and EP's therapeutic potential.

Methods: In the current study, an untargeted metabolomics approach was used to reveal brain metabolism changes in rats 24 h after a controlled cortical impact (CCI) injury, with or without EP treatment. Using principal component analysis (PCA), volcano plots, Random Forest and pathway analysis we differentiated the brain metabolomes of CCI and sham injured animals treated with saline (Veh) or EP, identifying key metabolites and pathways affected by injury. Additionally, the effect of EP on the non-injured brain was also explored.

Results: PCA showed a clear separation of the four study groups (sham-Veh, CCI-Veh, sham-EP, CCI-EP) based on injury. Following CCI injury (CCI-Veh), 109 metabolites belonging to the amino acid, carbohydrate, lipid, nucleotide, and xenobiotic families exhibited a twofold change at 24 h compared to the sham-Veh group, with 93 of these significantly increasing and 16 significantly decreasing (p < 0.05). CCI animals were treated with EP (CCI-EP) showed only 5 metabolites in the carbohydrate, amino acids, peptides, nucleotides, lipids, and xenobiotics super families that exhibited a twofold change, compared to the CCI-Veh group (p < 0.05). In the non-injured brain, EP treatment (sham-EP) resulted in a twofold change in 6 metabolites within the amino acid, peptide, nucleotide, and lipid super families compared to saline treated sham animals (sham-Veh, p < 0.05).

Conclusions: This study delineates the unique metabolic signatures resulting from a CCI injury and those related to EP treatment in both the injured and non-injured brain, underscoring the metabolic adaptations to brain injury and the effects of EP. Our analysis uncovers significant shifts in metabolites associated with inflammation, energy metabolism, and neuroprotection after injury, and demonstrates how EP intervention after injury alters metabolites associated with mitigating inflammation and oxidative damage.

Background: Diabetes-associated cognitive dysfunction, characterized by hippocampal synaptic loss as an early pathological feature, seriously threatens patients' quality of life. Synapses are dynamic structures, and hormones play important roles in modulating the formation and elimination of synapses. The pituitary, the master gland of the body, releases several hormones with multiple roles in hippocampal synaptic regulation. In this study, we aimed to explore the relationship between pituitary hormones and cognitive decline in diabetes.

Methods: A total of 744 patients with type 2 diabetes (T2DM) (445 men and 299 postmenopausal women) who underwent serum pituitary hormone level assessments, comprehensive cognitive evaluations and MRI scans were enrolled. Dynamic diet interventions were applied in both chow diet-fed mice and high-fat diet (HFD)-fed diabetic mice. The cognitive performance and hippocampal pathology of prolactin (PRL)-knockout mice, neuronal prolactin receptor (PRLR)-specific knockout mice and microglial PRLR-specific knockout mice were assessed. Microglial PRLR-specific knockout mice were fed an HFD to model diabetes. Diabetic mice received an intracerebroventricular infusion of recombinant PRL protein or vehicle.

Results: This clinical study revealed that decreased PRL levels were associated with cognitive impairment and hippocampal damage in T2DM patients. In diabetic mice, PRL levels diminished before hippocampal synaptic loss and cognitive decline occurred. PRL loss could directly cause cognitive dysfunction and decreased hippocampal synaptic density. Knockout of PRLR in microglia, rather than neurons, induced hippocampal synaptic loss and cognitive impairment. Furthermore, blockade of PRL/PRLR signaling in microglia exacerbated abnormal microglial phagocytosis of synapses, further aggravating hippocampal synaptic loss and cognitive impairment in diabetic mice. Moreover, PRL infusion reduced microglia-mediated synaptic loss, thereby alleviating cognitive impairment in diabetic mice.

Conclusion: PRL is associated with cognitive dysfunction and hippocampal damage in T2DM patients. In diabetes, a decrease in PRL level drives hippocampal synaptic loss and cognitive impairment by increasing microglia-mediated synapse engulfment. Restoration of PRL levels ameliorates cognitive dysfunction and hippocampal synaptic loss in diabetic mice.

The aging of the central nervous system(CNS) is a primary contributor to neurodegenerative diseases in older individuals and significantly impacts their quality of life. Neuroinflammation, characterized by activation of microglia(MG) and release of cytokines, is closely associated with the onset of these neurodegenerative diseases. The activated status of MG is modulated by specifically programmed metabolic changes under various conditions. Succinylation, a novel post-translational modification(PTM) mainly involved in regulating mitochondrial energy metabolism pathways, remains unknown in its role in MG activation and aging. In the present study, we found that succinylation levels were significantly increased both during aging and upon lipopolysaccharide-induced(LPS-induced) MG activation undergoing metabolic reprogramming. Up-regulated succinylation induced by sirtuin 5 knockdown(Sirt5 KD) in microglial cell line BV2 resulted in significant up-regulation of aging-related genes, accompanied by impaired mitochondrial adaptability and a shift towards glycolysis as a major metabolic pathway. Furthermore, after LPS treatment, Sirt5 KD BV2 cells exhibited increased generation of reactive oxygen species(ROS), accumulation of lipid droplets, and elevated levels of lipid peroxidation. By employing immunoprecipitation, introducing point mutation to critical succinylation sites, and conducting enzyme activity assays for succinate dehydrogenase(SDH) and trifunctional enzyme subunit alpha(ECHA), we demonstrated that succinylation plays a regulatory role in modulating the activities of these mitochondrial enzymes. Finally, down-regulation the succinylation levels achieved through administration of succinyl phosphonate(SP) led to amelioration of MG senescence in vitro and neuroinflammation in vivo. To our knowledge, our data provide preliminary evidence indicating that up-regulated succinylation modifications elicit a senescence phenotype in MG through alterations in energy metabolism. Moreover, these findings suggest that manipulation of succinylation levels may offer valuable insights into the treatment of aging-related neuroinflammation.

Background: Despite great advances in proliferative diabetic retinopathy (PDR) therapy over the last decades, one third of treated patients continue to lose vision. While resident vitreous macrophages called hyalocytes have been implicated in the pathophysiology of vitreoretinal proliferative disease previously, little is known about their exact role in PDR. In this study, we address molecular and cellular alterations in the vitreous of PDR patients as a means towards assessing the potential contribution of hyalocytes to disease pathogenesis.

Results: A total of 55 patients were included in this study encompassing RNA-Sequencing analysis of hyalocytes isolated from the vitreous of PDR and control patients, multiplex immunoassay and ELISA analyses of vitreous samples from PDR and control patients, as well as isolation and immunohistochemical staining of cultured porcine hyalocytes. Transcriptional analysis revealed an enhanced inflammatory response of hyalocytes contributing to the cytokine pool within the vitreous of PDR patients by expressing interleukin-6, among others. Further, increased angiopoietin-2 expression indicated that hyalocytes from PDR patients undergo a proangiogenic shift and may thus mediate the formation of retinal neovascularizations, the hallmark of PDR. Finally, RNA-Sequencing revealed an upregulation of factors known from hemoglobin catabolism in hyalocytes from PDR patients. By immunohistochemistry, cultured porcine hyalocytes exposed to red blood cells were shown to engulf and phagocytose these, which reveals hyalocytes' potential to dispose of erythrocytes. Thus, our data suggest a potential role for vitreous macrophages in erythrophagocytosis and, thereby, clearance of vitreous hemorrhage, a severe complication of PDR.

Conclusion: Our results strongly indicate a critical role for vitreous hyalocytes in key pathophysiological processes of proliferative diabetic retinopathy: inflammation, angiomodulation and erythrophagocytosis. Immunomodulation of hyalocytes may thus prove an essential novel therapeutic approach in diabetic vitreoretinal disease.

Postoperative cognitive dysfunction (POCD) is a frequent neurological complication encountered during the perioperative period with unclear mechanisms and no effective treatments. Recent research into the pathogenesis of POCD has primarily focused on neuroinflammation, oxidative stress, changes in neural synaptic plasticity and neurotransmitter imbalances. Given the high-energy metabolism of neurons and their critical dependency on mitochondria, mitochondrial dysfunction directly affects neuronal function. Additionally, as the primary organelles generating reactive oxygen species, mitochondria are closely linked to the pathological processes of neuroinflammation. Surgery and anesthesia can induce mitochondrial dysfunction, increase mitochondrial oxidative stress, and disrupt mitochondrial quality-control mechanisms via various pathways, hence serving as key initiators of the POCD pathological process. We conducted a review on the role and potential mechanisms of mitochondria in postoperative cognitive dysfunction by consulting relevant literature from the PubMed and EMBASE databases spanning the past 25 years. Our findings indicate that surgery and anesthesia can inhibit mitochondrial respiration, thereby reducing ATP production, decreasing mitochondrial membrane potential, promoting mitochondrial fission, inducing mitochondrial calcium buffering abnormalities and iron accumulation, inhibiting mitophagy, and increasing mitochondrial oxidative stress. Mitochondrial dysfunction and damage can ultimately lead to impaired neuronal function, abnormal synaptic transmission, impaired synthesis and release of neurotransmitters, and even neuronal death, resulting in cognitive dysfunction. Targeted mitochondrial therapies have shown positive outcomes, holding promise as a novel treatment for POCD.

Circulating miR-30c-2-3p has been closely related to vascular diseases, however, its role and underlying mechanisms in ischemic stroke remained unclear. Our study addressed this gap by observing elevated levels of exosomal miR-30c-2-3p in patients with acute ischemic stroke due to large artery atherosclerosis. Further investigation revealed that these exosomal miR-30c-2-3p primarily originated from macrophages within atherosclerotic plaques, exacerbating ischemic stroke by targeting microglia. Exosomes enriched with miR-30c-2-3p increased microglial inflammatory properties in vivo and aggravated neuroinflammation by inhibiting SMAD2. In summary, our findings revealed a novel mechanism whereby macrophage-derived foam cells within atherosclerotic plaques secrete exosomes with high levels of miR-30c-2-3p, thus aggravate brain damage during ischemic stroke, which serves as crucial link between the periphery and brain.

Neurodegeneration and neuroinflammation are key components in the pathogenesis of Japanese Encephalitis caused by Japanese Encephalitis Virus (JEV) infection. The N-methyl-D-aspartate (NMDA)-type glutamate receptor displays excitatory neurotoxic and pro-inflammatory properties in a cell context-dependent manner. Herein, potential roles of the NMDA receptor in excitatory neurotoxicity and neuroinflammation and effects of NMDA receptor blockade against JEV pathogenesis were investigated in rat microglia, neuron/glia, neuron cultures, and C57BL/6 mice. In microglia, JEV infection induced glutamate release and activated post-receptor NMDA signaling, leading to activation of Ca²⁺ mobilization and Calcium/Calmodulin-dependent Protein Kinase II (CaMKII), accompanied by pro-inflammatory NF-κB and AP-1 activation and cytokine expression. Additionally, increased Dynamin-Related Protein-1 protein phosphorylation, NAPDH Oxidase-2/4 expression, free radical generation, and Endoplasmic Reticulum stress paralleled with the reactive changes of microglia after JEV infection. JEV infection-induced biochemical and molecular changes contributed to microglia reactivity and pro-inflammatory cytokine expression. NMDA receptor antagonists MK801 and memantine alleviated intracellular signaling and pro-inflammatory cytokine expression in JEV-infected microglia. JEV infection induced neuronal cell death in neuron/glia culture associated with the concurrent production of pro-inflammatory cytokines. Conditioned media of JEV-infected microglia compromised neuron viability in neuron culture. JEV infection-associated neuronal cell death was alleviated by MK801 and memantine. Activation of NMDA receptor-related inflammatory changes, microglia activation, and neurodegeneration as well as reversal effects of memantine were revealed in the brains of JEV-infected mice. The current findings highlight a crucial role of the glutamate/NMDA receptor axis in linking excitotoxicity and neuroinflammation during the course of JEV pathogenesis, and proposes the anti-inflammatory and neuroprotective potential of NMDA receptor blockade.