Journal of Neuroinflammation最新文献

Demyelination occurs with aging and is exacerbated in neurodegenerative diseases. During demyelination, microglia upregulate expression of APOE, the gene encoding for the brain's primary lipid transport protein apolipoprotein E (ApoE), which also mediates microglial engulfment and elimination of myelin debris. Compared to the E3 allele of APOE, the E2 allele decreases risk for Alzheimer's disease (AD), while the E4 allele increases AD risk and is associated with an increased severity and progression of multiple sclerosis. Previous work shows that mice expressing E2 exhibit improved microglial function and remyelination compared to mice expressing E4. However, whether microglial-derived APOE is responsible for driving these differences following demyelination, and if microglia-selective expression of E2 is sufficient to provide protection, is unknown. We sought to determine if microglia-specific replacement of the E4 allele with E2 can rescue myelin loss and promote remyelination, even in the presence of continued E4 expression by other central nervous system (CNS) cells. Using a novel APOE allelic "switch" model in which we can induce a replacement of E4 with E2 exclusively in microglia, we characterize the glial cell response and lipid profile of mice that underwent either lysophosphatidylcholine (LPC) or cuprizone (CPZ)-induced demyelination and subsequent remyelination. We found that although alterations to the brain lipid profile were subtle, microglial E2 replacement significantly improved remyelination, lessened microgliosis, and decreased astrocytic lipid droplet load following CPZ-remyelination. Our results indicate that microglia-specific E2 expression, in the presence of continued E4 expression, may provide protection against myelin loss via both cell-autonomous and non-autonomous immunometabolic mechanisms.

Background: Synaptic abnormalities are hallmark pathological features of autism spectrum disorders (ASD), contributing to the behavioral impairments frequently observed in these neurodevelopmental conditions. Microglia, as the brain's primary immune cells, are essential for synaptic refinement during adolescent development. Disrupted microglia-dependent synapse remodeling has been implicated in pathophysiology of ASDs, however, the underlying mechanisms remain incompletely elucidated. In this context, repetitive unidirectional spinal tactile stimulation (RSTS) has emerged as a promising non-invasive therapeutic strategy. This study aims to explore whether and how RSTS enhances microglia-dependent synapse remodeling in the medial prefrontal cortex (mPFC) during adolescent development in ASD mice, with a specific focus on the role of Brain and Muscle ARNT-Like 1 (Arntl1), a core circadian protein crucial for regulating this process.

Methods: ASD mice underwent RSTS treatment during adolescent brain for 21 days, administered twice daily for 10 min per session. Behavioral changes were evaluated using the three-chamber social interaction and open field tests. Synapse number and morphology were assessed through Golgi staining. Microglia-dependent synapse remodeling ability was analyzed using immunofluorescence and Western blot. Furthermore, the molecular mechanism was investigated using single-nucleus RNA sequencing (snRNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq). Finally, the role of Bmal1 was validated, confirming its involvement in the enhancement of RSTS during adolescent brain in ASD.

Results: RSTS was found to alleviate autistic-like behaviors in adolescent ASD mice. Results from snRNA-seq and ChIP-seq indicated that the therapeutic effects of RSTS may be mediated through microglial Bmal1 and its role in the transcriptional regulation of microglia-dependent synapse remodeling. Furthermore, in vivo experiments confirmed that RSTS enhances microglia-dependent synapse remodeling in mPFC of adolescent ASD mice via Bmal1. These findings suggested that Bmal1 serves as a critical target of RSTS in facilitating microglia-dependent synapse remodeling during the adolescent brain developmental period in ASD mice.

Conclusion: Our findings suggest that the therapeutic effects of RSTS are potentially mediated through the modulation of microglial Bmal1-dependent synapse remodeling and the regulation of synaptic proteins and the complement system. These results provide novel empirical evidence for RSTS in restoring synaptic balance and offer valuable insights into its potential as an intervention for ASD.

Background and objectives: TBI-induced acute lung injury (TBI-ALI), with an incidence rate of 22-25%, represents a critical determinant of secondary mortality. Remimazolam is a novel sedative that has shown potential for anti-inflammatory effects. However, whether remimazolam ameliorates TBI-ALI remains unclear.

Methods: We established a controlled cortical impact (CCI) mouse model of TBI and combined ATF3 knockdown with remimazolam administration to assess lung injury. Subsequently, we employed WB and mRNA-seq techniques to investigate the potential molecular mechanisms of remimazolam's effect on ALI. Finally, we conducted in vivo and in vitro experiments to validate our findings on these mechanisms.

Results: Remimazolam significantly mitigated TBI-ALI. Western blot and mRNA sequencing (mRNA-seq) analyses demonstrated that remimazolam inhibited post-TBI upregulation of activating transcription factor 3 (ATF3) and activation of the NOD-like receptor signaling pathway. In vitro experiments revealed that remimazolam reduced pyroptosis activation in mouse alveolar epithelial cells (MLE-12) by suppressing ATF3 expression, concurrently attenuating degradation of junctional proteins (ZO-1/E-cadherin). In vivo studies confirmed that remimazolam inhibited pulmonary epithelial pyroptosis and preserved blood-air barrier (BAB) integrity post-TBI, ultimately alleviating ALI progression.

Conclusion: Remimazolam mitigates TBI-ALI by suppressing post-traumatic ATF3 upregulation, thereby reducing NLRP3 inflammasome activation. This attenuates alveolar epithelial pyroptosis, preserves junctional protein integrity and BAB function, and ultimately ameliorates pulmonary pathology. These findings position remimazolam as a key therapeutic agent for neurotrauma-induced secondary organ dysfunction.

Acute neuroinflammation rapidly activates brain immune responses, but its lasting effects on microglia are unclear. Using systemic LPS administration and LCMV-Armstrong infection, we found that blood-brain barrier disruption and cytokine shifts resolved within 30 days, yet microglial recovery was incomplete-marked by persistent numerical loss and an IFN-γ-low phenotype in the LPS model and reduced relative abundance in the LCMV model. Single-cell RNA sequencing revealed sustained transcriptional alterations, including disease-associated microglia (DAM) features and a distinct recovery-biased population. These acute signatures overlapped with profiles from Alzheimer's model mice and were enriched in human microglia from multiple sclerosis, Alzheimer's disease, and other neuroinflammatory conditions. Although our observation period was shorter than the chronic course of these diseases, the persistence of disease-like microglial states suggests that transient inflammation can prime the brain for long-term vulnerability. Targeting this primed state may offer new strategies to prevent or mitigate neurodegenerative pathology.

Background: Traumatic brain injury (TBI) triggers persistent gut microbiome dysbiosis characterized by depletion of short-chain fatty acid (SCFA)-producing bacteria. However, the link between SCFA depletion and long-term neurologic impairment (LTNI) after TBI remains unclear. Previously, we and others noted the involvement of metabolite-sensing receptors and SCFA ligands in mouse models of neurodegenerative diseases, including Alzheimer's. Here, we further investigated SCFA-mediated neuroprotection in LTNI at both microbiome and single-cell resolution using the controlled cortical impact (CCI) model of TBI with a high-yielding SCFA diet to examine their mechanistic role in pathogenesis.

Methods: C57BL6/J mice were randomized to CCI (6 m/s, 2 mm) or sham surgery. Following surgery, mice were randomized to a study diet based on a balanced modification of the AIN93-G diet containing either 15% high amylose maize starch (HAMS) control diet or acetylated and butyrylated HAMS (HAMSAB) for 6 months to model increased SCFA production by bacterial fermentation in the gut. Morris water maze test and nesting assessment were performed at 1, 3, and 6 months after injury. The longitudinal gut microbiome changes were investigated by 16 S rRNA amplicon and metagenomic sequencing of fecal pellets at baseline, 1 month, and 6 months post-injury. At 6 months, pericontusional tissue was collected for single-cell RNA-sequencing following the 10X Genomics protocol or histologic analysis.

Results: Compared to the HAMS control diet, HAMSAB diet remodeled the CCI murine gut microbiome at an early phase, increased various SCFA-producing taxa, and attenuated neurologic deficits up to 6 months after CCI. In mice fed HAMSAB diet, single-cell transcriptomics and pathway analysis identified the promotion of neurogenesis, including increased doublecortin-positive immature neurons. In myeloid cells, HAMSAB induced an anti-inflammatory phenotype, inhibiting pro-inflammatory signaling interaction such as midkine signaling, and promoted differentiation to disease-associated microglia (DAM). Simultaneously, SCFAs reduced neurodegenerative pathway activity in neurons and glial cells and reduced phosphorylated tau deposition in pericontusional cortex.

Conclusions: Diet-facilitated microbial production of acetate and butyrate attenuates behavioral deficits of LTNI after TBI and produces enduring benefits at the single-cell level on the neuro-inflammatory and neuro-progenitor responses. This therapeutic approach could have a broader potential to prevent neurodegenerative disease.

Breakdown of the blood-retina barrier is a key event in the progression of retinal vascular diseases. Microglia, the resident immune cells of the retina and central nervous system, respond rapidly to vascular injury, yet how hyperglycemia affects this protective function remains unclear. In this study, we combined intravitreal injection of lipopolysaccharide (LPS) with streptozotocin to mimic both acute inflammation under hyperglycemic conditions. LPS triggered a robust increase in microglia-blood vessel interactions (MVIs), mediated by P2Y12 receptor signaling, as confirmed by both pharmacological inhibition and genetic knockout of P2Y12. Live ex vivo retinal imaging demonstrated that microglial processes rapidly converged on injured vessels within 30 min in a P2Y12-dependent manner. However, four weeks of hyperglycemia significantly blunted this MVI response. We found that hyperglycemia elevated circulating norepinephrine (NE), which infiltrated the retina and suppressed MVIs through activation of microglial β2-adrenergic receptors (ADRB2). Ex vivo imaging further showed that pharmacological ADRB2 activation impaired microglial process convergence to sites of vascular injury. Together, these findings reveal that NE-ADRB2 signaling antagonizes P2Y12-mediated microglial engagement with leaky vessels, contributing to BRB breakdown. This study uncovers a novel neuroimmune-vascular mechanism by which hyperglycemia compromises retinal vascular repair and identifies potential therapeutic targets for retinal vascular disorders.