Journal of Neuroinflammation最新文献

Astrocytes are key regulators of neuroinflammation in multiple sclerosis (MS). Electroacupuncture (EA), a safe and cost-effective adjuvant therapy, has shown benefits in neurodegenerative diseases, but its astrocyte-related mechanisms remain unclear. Here, we demonstrated that EA at ST36 alleviated blood-brain barrier (BBB) disruption and neuroinflammation during the peak period of experimental autoimmune encephalomyelitis (EAE). Additionally, EA at ST36 upregulated the expression of α-melanocyte-stimulating hormone (α-MSH) and its receptor melanocortin-4 receptor (MC4R) in spinal astrocytes. Pharmacological studies showed that MC4R agonist RO27-3225 mimicked the therapeutic effects of EA, whereas MC4R antagonist TCMCB07 weakened EA-mediated BBB protection and neuroinflammation suppression. Moreover, astrocyte-specific silencing of MC4R via adeno-associated virus (AAV) weakened EA-mediated BBB protection and neuroinflammation suppression. RNA-sequencing (RNA-seq) and western blot (WB) revealed that EA exerts neuroprotective effects by activating MC4R to inhibit MAPK and NF-κB signaling pathways. Moreover, in MC4R-overexpressing astrocytes, α-MSH and RO27-3225 reduced inflammation responses, while TCMCB07 reversed the effects by MAPK/NF-κB signaling pathways. Collectively, our findings identify astrocytic MC4R as a critical mediator of EA-driven neuroprotection by suppressing MAPK/NF-κB signaling, providing mechanistic insight and a promising therapeutic target for EAE and other neuroinflammatory disorders.

Gut microbiota dysbiosis has been implicated in the pathogenesis of mastitis. While the vagus nerve exerts well-documented anti-inflammatory effects and modulates gut microbiota, its potential influence on mastitis progression via gut microbiota modulation remains unclear. To investigate this, we employed vagus nerve stimulation (VNS) in Staphylococcus aureus (S. aureus)-induced mastitis in mice. We demonstrate that VNS significantly attenuated mammary gland inflammation and restored epithelial barrier integrity following S. aureus challenge. Crucially, antibiotic depletion of the gut microbiota abrogated the protective effects of VNS, and fecal microbiota transplantation (FMT) from VNS-treated mice conferred protection against mastitis, establishing a causal role for the gut microbiota in mediating the VNS effect. Specifically, VNS markedly increased the abundance of Muribaculaceae. in the gut. Replenishment with S24-7, a representative strain of this genus, alleviated S. aureus-induced mammary gland inflammation in mice. Transcriptomic analysis revealed that S24-7 exerted its effects by activating peroxisome proliferator-activated receptor gamma (PPARγ), which subsequently suppressed the NF-κB/NLRP3 signaling pathway. Overall, our findings suggest that targeting the vagus nerve - mediated Muribaculaceae/PPARγ axis may represent a promising strategy for mastitis treatment.

Parkinson's disease is a common neurodegenerative disease related to both genetic and environmental insults. Epidemiological studies have linked Helicobacter pylori (H. pylori) infection to Parkinson's disease risk, but the underlying mechanisms of this association remain unclear. In this study, we investigated whether chronic infection with a pathogenic H. pylori strain could induce α-synuclein aggregation or neurodegeneration, and whether infection clearance mitigates these effects. We also assessed whether H. pylori infection exacerbates α-synuclein pathology and neuron loss when combined with seeding of α-synuclein pathology. We find that chronic H. pylori infection induces a sustained immune response in the gut and plasma that leads to mild brain inflammation and dopaminergic neuron loss, independent of α-synuclein pathology. These effects are attenuated by eradication of the infection. In mice with α-synuclein pathology induced by pre-formed fibrils, H. pylori does not further exacerbate the extent of pathology or neuronal death. Together, these results suggest that H. pylori infection can lead to neurodegeneration through inflammatory mechanisms independent of α-synuclein aggregation. Our findings offer mechanistic insights into how pathogens could influence the risk and progression of Parkinson's disease.

Cognitive impairment is a prevalent extrapulmonary manifestation of COPD. However, existing reviews have not yet systematically linked COPD-related dysregulation of brain functional networks with clinical indicators. This review bridges this gap by elucidating the pathway from pulmonary pathology to cognitive deficits via central network dysfunction, synthesizing evidence across four dimensions: clinical manifestations; physiological and pathological mechanisms; fMRI-based brain network disorders; and promising treatments. Chronic hypoxia-induced neuroinflammation, oxidative stress, and systemic inflammation propagated via the lung-brain axis were the main pathogenesis of COPD-CI. Cognitive deficits in COPD patients primarily manifest as executive function and visuospatial impairment, with some reality distinctive neural network features showing aberrant functional connectivity between the default mode network and visual network. Long-term oxygen therapy, anti-inflammatory regimens, and cognitive rehabilitation demonstrate benefits in improving cognition. Large sample, cross-sectional study is needed in the future studies, and multimodal neuroimaging should be used to delineate spatiotemporal network dynamics in COPD-CI.

Neuroinflammation is implicated in the pathogenesis of Amyotrophic Lateral Sclerosis (ALS). Amongst potential innate immune mediators of disease, Type I interferon (IFN-I) could play an important role due to its ability to inhibit protein synthesis and affect neuronal synapses and metabolism. These effects could be cell intrinsic or non-cell autonomous mediated by glia or immune cells. We examined IFN-I in rNLS8 mice that have been engineered to express doxycycline suppressible human Transactive response DNA binding protein 43 kDa (hTDP-43) with a defective nuclear localization signal (hTDP-43ΔNLS) regulated by the neurofilament heavy chain (NEFH) promoter. Following induction of hTDP-43ΔNLS in rNLS8 mice, we observed upregulation of IFN-I stimulated genes (ISG) and, specifically, activation of the DNA sensor, cyclic GMP-AMP synthase (cGAS), as determined by mass spectrometry identification of the cyclic dinucleotide, cGAMP, in whole brain. To determine the cellular source of IFN-I, we performed single nucleus RNA sequencing of whole brain. We observed that ISG were most highly upregulated in astrocytes suggesting that astrocytes themselves were largely responsible for IFN-I production and / or response in rNLS8 mice. This observation was confirmed by immunohistochemical and immunofluorescence staining of IFN-I stimulated proteins in astrocytes in the cerebrum, especially in the hippocampus. These results point to a pivotal role of astrocytes in responding to cell damage at a relatively early phase of disease which prior studies have shown is partially reversible.

Chronic stress precipitates depression, yet how gut-immune-brain interactions translate stress into mood pathology remains unclear. We tested the hypothesis that stress-primed small intestinal γδ T cells drive hippocampal mitochondrial dysfunction and depression-like behavior via interleukin-17A (IL-1A). In mice exposed to chronic restraint stress (CRS), we combined behavioral assays (open-field, sucrose-preference, tail-suspension, forced-swim), 16S rRNA profiling, fecal microbiota transplantation, Kaede photoconversion, conditional CD8α deletion in γδ T cells, hippocampal IL-17A overexpression, rapamycin treatment, and administration of the antidepressant arketamine. CRS increased gut and brain permeability, induced gut-microbiota dysbiosis, and promoted migration of small intestinal CD8α⁺ γδ T17 cells to the meninges and brain; γδ T cells were the predominant IL-17A source in the brain. Kaede tracing confirmed an intestinal origin, and CRS-associated microbiota alone transferred γδ T cell trafficking and depression-like behavior to recipients. In the hippocampus, CRS elevated IL-17A and impaired PINK1/Parkin-mediated mitophagy (decreased PINK1, Parkin, Beclin-1, and LC3B-II/I; increased p62), reduced ATP, and produced mitochondrial and synaptic ultrastructural deficits. IL-17A overexpression further worsened mitophagy and behavior, whereas rapamycin restored both. Conditional deletion of CD8α in γδ T cells reduced brain γδ T17 infiltration, lowered hippocampal IL-17A, rescued mitophagy and synapses, and improved behavior. Arketamine normalized dysbiosis and barrier markers, curtailed γδ T cell trafficking, decreased hippocampal IL-17A, restored mitophagy, and alleviated depression-like behavior in both sexes. These findings delineate a stress-responsive microbiota-γδ T cell-IL-17A pathway that compromises hippocampal mitophagy and identify arketamine as a candidate modulator of this axis, nominating mitophagy and γδ T cell trafficking as translational targets.