Pleiotrophin ameliorates age-induced adult hippocampal neurogenesis decline and cognitive dysfunction.

Cognitive impairment has been associated with an age-related decline in adult hippocampal neurogenesis (AHN). The molecular basis of declining neurogenesis in the aging hippocampus remains to be elucidated. Here, we show that pleiotrophin (PTN) expression is decreased with aging in neural stem and progenitor cells (NSPCs). Mice lacking PTN exhibit impaired AHN accompanied by poor learning and memory. Mechanistically, we find that PTN engages with protein tyrosine phosphatase receptor type Z1 (PTPRZ1) to promote NSPC proliferation and differentiation by activating AKT signaling. PTN overexpression or pharmacological activation of AKT signaling in aging mice restores AHN and alleviates relevant memory deficits. Importantly, we also find that PTN overexpression improves impaired neurogenesis in senescence-accelerated mouse prone 8 (SAMP8) mice. We further confirm that PTN is required for enriched environment-induced increases in AHN. These results corroborate the significance of AHN in aging and reveal a possible therapeutic intervention by targeting PTN.

Triptolide improves Alzheimer's disease by regulating the NF­κB signaling pathway through the lncRNA NEAT1/microRNA 361­3p/TRAF2 axis.

Alzheimer's disease (AD) is the most common type of dementia and is a serious social and medical problem threatening human health. The present study investigated the effect and underlying action mechanism of triptolide (Tri) on AD progression. Reverse transcription-quantitative PCR and western blotting analysis were used to determine the changes in RNA expression and levels of NF-κB signaling pathway proteins before and after lipopolysaccharide (LPS) induction. Nucleocytoplasmic separation experiments determined the intracellular localization of long non-coding RNA (lncRNA) nuclear paraspeckle assembly transcript 1 (NEAT1). A dual-luciferase assay was used to analyze the binding between NEAT1 and microRNA (miRNA/miR)-361 or tumor necrosis factor receptor-associated factor 2 (TRAF2) and miR-361-3p and RNA pull-down was used to analyze the binding between NEAT1 and miR-361-3p. Cell Counting Kit-8, flow cytometry and ELISA were used to detect the effects of interaction between Tri and NEAT1/miR-361-3p/TRAF2 on cell viability, apoptosis and inflammatory factor levels, respectively. The results showed that LPS-mediated human microglial clone 3 cell line (HMC3) viability decreased and apoptosis and inflammatory factors (IL-1ß, IL-6, IL-18 and TNF-α) increased. Tri inhibited LPS-mediated effects in a dose-dependent manner by downregulating NEAT1 expression. NEAT1 is highly expressed in the cytoplasm and reduces the transcription and translation of downstream TRAF2 by acting as a competitive endogenous RNA that adsorbs miR-361-3p. LPS-mediated HMC3 cell injury, inflammation and activation of NF-κB signaling were partially reversed in presence of Tri. The miR-361-3p mimic promoted the Tri effect and overexpression of (ov)-NEAT1 partially reversed the Tri-miR-361-3p combined effect. The effects of ov-NEAT1 were partially attenuated by small interfering (si)-TRAF2. Overall, Tri inhibited the LPS-induced decrease in viability, increase in apoptosis and inflammation and activation of NF-κB signaling in HMC3 cells. Tri regulation affected the NEAT1/miR-361-3p/TRAF2 axis. These findings suggested a potential therapeutic role for Tri in the clinical management of AD by modulating this molecular axis.

Transfer of patient's peripheral blood mononuclear cells (PBMCs) disrupts blood-brain barrier and induces anti-NMDAR encephalitis: a study of novel humanized PBMC mouse model.

BACKGROUND: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is a severe autoimmune neuropsychiatric disease. Brain access of anti-NMDAR autoantibody through the blood-brain barrier (BBB) is essential for pathogenesis. Most previous animal models limit the investigation of etiologies of BBB damage in patients. METHODS: In this study, we established a novel humanized mouse model of anti-NMDAR encephalitis by intraperitoneal injection of patients' peripheral blood mononuclear cells (PBMCs) into BALB/c Rag2-/-Il2rg-/-SirpαNODFlk2-/- mice. RESULTS: We found that engraftment of patients' PBMCs not only produced potent anti-GluN1 autoantibodies, but also disrupted BBB integrity to allow brain access of autoantibodies, resulting in a hyperactive locomotor phenotype, anxiety- and depressive-like behaviors, cognitive deficits, as well as functional changes in corresponding brain regions. Transcriptome analysis suggested an exaggerated immune response and impaired neurotransmission in the mouse model and highlighted Il-1ß as a hub gene implicated in pathological changes. We further demonstrated that Il-1ß was produced by endothelial cells and disrupted BBB by repressing tight junction proteins. Treatment with Anakinra, an Il-1 receptor antagonist, ameliorated BBB damage and neuropsychiatric behaviors. CONCLUSIONS: Our study provided a novel and clinically more relevant humanized mouse model of anti-NMDAR encephalitis and revealed an intrinsic pathogenic property of the patient's lymphocytes.

Macrophage lineage cells-derived migrasomes activate complement-dependent blood-brain barrier damage in cerebral amyloid angiopathy mouse model.

Accumulation of amyloid beta protein (Aß) in brain vessels damages blood brain barrier (BBB) integrity in cerebral amyloid angiopathy (CAA). Macrophage lineage cells scavenge Aß and produce disease-modifying mediators. Herein, we report that Aß40-induced macrophage-derived migrasomes are sticky to blood vessels in skin biopsy samples from CAA patients and brain tissue from CAA mouse models (Tg-SwDI/B and 5xFAD mice). We show that CD5L is packed in migrasomes and docked to blood vessels, and that enrichment of CD5L impairs the resistance to complement activation. Increased migrasome-producing capacity of macrophages and membrane attack complex (MAC) in blood are associated with disease severity in both patients and Tg-SwDI/B mice. Of note, complement inhibitory treatment protects against migrasomes-mediated blood-brain barrier injury in Tg-SwDI/B mice. We thus propose that macrophage-derived migrasomes and the consequent complement activation are potential biomarkers and therapeutic targets in CAA.

Bone Marrow Mesenchymal Stem Cell-Derived Dermcidin-Containing Migrasomes enhance LC3-Associated Phagocytosis of Pulmonary Macrophages and Protect against Post-Stroke Pneumonia.

Pneumonia is one of the leading causes of death in patients with acute ischemic stroke (AIS). Antibiotics fail to improve prognosis of patients with post-stroke pneumonia, albeit suppressing infection, due to adverse impacts on the immune system. The current study reports that bone marrow mesenchymal stem cells (BM-MSC) downregulate bacterial load in the lungs of stroke mice models. RNA-sequencing of the lung from BM-MSC-treated stroke models indicates that BM-MSC modulates pulmonary macrophage activities after cerebral ischemia. Mechanistically, BM-MSC promotes the bacterial phagocytosis of pulmonary macrophages through releasing migrasomes, which are migration-dependent extracellular vesicles. With liquid chromatography-tandem mass spectrometry (LC-MS/MS), the result shows that BM-MSC are found to load the antibacterial peptide dermcidin (DCD) in migrasomes upon bacterial stimulation. Besides the antibiotic effect, DCD enhances LC3-associated phagocytosis (LAP) of macrophages, facilitating their bacterial clearance. The data demonstrate that BM-MSC is a promising therapeutic candidate against post-stroke pneumonia, with dual functions of anti-infection and immunol modulation, which is more than a match for antibiotics treatment.

FOXP3+ macrophage represses acute ischemic stroke-induced neural inflammation.

Proper termination of cell-death-induced neural inflammation is the premise of tissue repair in acute ischemic stroke (AIS). Macrophages scavenge cell corpses/debris and produce inflammatory mediators that orchestrate immune responses. Here, we report that FOXP3, the key immune-repressive transcription factor of Tregs, is conditionally expressed in macrophages in stroke lesion. FOXP3 ablation in macrophages results in detrimental stroke outcomes, emphasizing the beneficial role of FOXP3+ macrophages. FOXP3+ macrophages are distinct from the M1 or M2 subsets and display superactive efferocytic capacity. With scRNAseq and analysis of FOXP3-bound-DNA isolated with CUT & RUN, we show that FOXP3 facilitates macrophage phagocytosis through enhancing cargo metabolism. FOXP3 expression is controlled by macroautophagic/autophagic protein degradation in resting macrophages, while initiation of LC3-associated phagocytosis (LAP) competitively occupies the autophagic machineries, and thus permits FOXP3 activation. Our data demonstrate a distinct set of FOXP3+ macrophages with enhanced scavenging capability, which could be a target in immunomodulatory therapy against AIS.Abbreviations: ADGRE1/F4/80: adhesion G protein-coupled receptor E1; AIF1/Iba1: allograft inflammatory factor 1; AIS: acute ischemic stroke; ARG1: arginase 1; ATP: adenosine triphosphate; BECN1/Beclin1: Beclin 1, autophagy related; BMDM: bone marrow-derived macrophages; CKO: conditional knockout; CSF1/M-CSF: colony stimulating factor 1 (macrophage); CSF2/GM-CSF: colony stimulating factor 2; CSF3/G-CSF: colony stimulating factor 3; CUT & RUN: cleavage under targets and release using nuclease; CyD: cytochalasin D; DAMP: danger/damage-associated molecular pattern; DIL: dioctadecyl-3,3,3,3-tetramethylin docarbocyanine; ELISA: enzyme linked immunosorbent assay; GO: Gene Ontology; FCGR3/CD16: Fc receptor, IgG, low affinity III; HMGB1: high mobility group box 1; IFNG/IFNγ: interferon gamma; IP: immunoprecipitation; KEGG: Kyoto Encyclopedia of Genes and Genomes; ITGAM/CD11b: integrin subunit alpha M; ITGAX/CD11c: integrin subunit alpha X; LAP: LC3-associated phagocytosis; LC-MS: liquid chromatography-mass spectrometry; LPS: lipopolysaccharide; MRC1/CD206: mannose receptor, C type 1; O4: oligodendrocyte marker O4; PBMC: peripheral blood mononuclear cells; RBC: red blood cells; PTPRC/CD45: protein tyrosine phosphatase, receptor type, C; RBFOX3/NeuN: RNA binding protein, fox 1 homolog (C. elegans) 3; RUBCN/Rubicon: RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; scRNAseq: single cell RNA sequencing; SQSTM1/p62 (sequestosome 1); TGFB/TGFß: transforming growth factor, beta; tMCAO: transient middle cerebral artery occlusion; TNF/TNFα: tumor necrosis factor; Treg: regulatory T cell.

Neutrophil Nanovesicle Protects against Experimental Autoimmune Encephalomyelitis through Enhancing Myelin Clearance by Microglia.

Timely clearance of myelin debris is the premise of neuroinflammation termination and tissue regeneration in multiple sclerosis (MS). Microglia are the main scavengers of myelin debris in MS lesions, but its phagocytic capability is limited in MS patients. Here, we develop neutrophil-derived nanovesicles (NNVs) to enhance the efficiency of myelin debris clearance in microglia for MS therapy. RNA sequencing (RNAseq) results demonstrate that NNVs treatment ameliorates lesional neuroinflammation of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. Consequently, EAE mice exhibit favorable neurological functions and white matter integrity after NNVs treatment. Specifically, NNVs treatment upregulates the expression of nuclear factor E2-related factor 2 (NRF2) in microglia, as revealed by Assay for Transposase Accessible Chromatin using sequencing (ATACseq). We also demonstrate that NRF2 can activate the transcription of RUBCN (RUN domain and cysteine-rich domain containing Beclin 1-interacting protein), which in turn enhances LC3-associated phagocytosis (LAP) in microglia. As a result, myelin debris engulfed by microglia can be efficiently catabolized in NNVs-treated EAE mice without obvious side effects. Together, this study proves that NNVs can modulate neuroinflammation by clearing myelin debris and is a promising MS treatment strategy.

Myelin oligodendrocyte glycoprotein-associated disease is associated with BANK1, RNASET2 and TNIP1 polymorphisms.

AIM: Here we aimed to compare association of common immune-related genetic variants with three autoimmune central nervous system (CNS) demyelinating diseases, namely myelin oligodendrocyte glycoprotein-associated disease (MOGAD), multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). METHODS: In this retrospective cross-sectional study, 26 common immune-related single nucleotide polymorphisms were genotyped in 102 patients with MOGAD, 100 patients with MS, 198 patients with NMOSD and 541 healthy control subjects recruited from Guangzhou, China. RESULTS: Among all tested genetic variations, one polymorphism, B cell scaffold protein with ankyrin repeats 1 (BANK1) rs4522865 was associated with multiple disorders, namely MOGAD (OR = 1.94, 95% CI:1.19-3.17, P = 0.0059) and NMOSD (OR = 1.69, 95% CI:1.17-2.45). Besides BANK1 rs4522865, two other non-HLA loci, ribonuclease T2 (RNASET2) rs9355610 (OR = 0.47, 95% CI: 0.26-0.85) and TNFAIP3 interacting protein 1 (TNIP1) rs10036748 (OR = 1.76, 95% CI: 1.16-2.71), were associated with MOGAD. In addition, NMOSD was associated with signal transducer and activator of transcription 4 (STAT4) rs7574865 (OR = 1.58, 95% CI: 1.12-2.24) and general transcription factor Iii (GTF2I) rs73366469 (OR = 1.60, 95% CI:1.12-2.29), while MS was associated with a killer cell lectin like receptor G1 (KLRG1) rs1805673 (OR = 0.61, 95% CI: 0.40-0.94) and T-box transcription factor 21 (TBX21) rs17244587 (OR = 2.25, 95% CI: 1.25-4.06). CONCLUSION: The current study suggests for the first time three non-HLA susceptibility loci for MOGAD. In addition, comparison of association of 26 immune-related polymorphisms with three autoimmune CNS demyelinating diseases demonstrates substantial difference in genetic basis of those disorders.

Cerebrospinal fluid cystatin C levels in patients with anti-NMDAR encephalitis and other neurological diseases.

BACKGROUND: Cystatin C has neuroprotective and immunomodulatory effects on the central nervous system. However, the role of cerebrospinal fluid (CSF) cystatin C in anti-N-methyl-d-aspartate receptor encephalitis (anti-NMDARE) remains unknown. METHODS: In this study, CSF levels of cystatin C were determined in 73 patients with anti-NMDARE; 496 patients with other neurological diseases, comprising 108 with neuromyelitis optica, 77 with multiple sclerosis, 71 with schizophrenia, 68 with cryptococcus meningitis or meningoencephalitis, 43 with tuberculous meningitis or meningoencephalitis, 43 with bacterial meningitis or meningoencephalitis (BM), 35 with Guillain-Barré syndrome, 23 with spinal cord injury (SCI), 14 with amyotrophic lateral sclerosis (ALS), and 14 with idiopathic epilepsy; and 136 control patients with non-inflammatory diseases. The associations of CSF cystatin C with anti-NMDARE and its clinical parameters were evaluated. RESULTS: CSF cystatin C levels were significantly lower in patients with anti-NMDARE than in patients with BM, SCI, and ALS, especially among those with poor functional status (modified Rankin Scale [mRS] ≥4). CSF cystatin C levels were also significantly lower in anti-NMDARE patients with poor functional status (mRS ≥4) than in those with good functional status (mRS <4). CSF cystatin C levels were significantly associated with mRS scores and CSF white blood cell counts in anti-NMDARE patients. CONCLUSIONS: CSF levels of cystatin C are decreased in anti-NMDARE patients and negatively associated with disease severity.

Enhancement pattern of demyelination-mimicking cerebral B-cell lymphoma.

BACKGROUND AND PURPOSE: Central nervous system (CNS) B-cell lymphoma-mimicking demyelinating diseases creates a diagnostic dilemma. This study aimed to determine the specific magnetic resonance imaging (MRI) features of CNS B-cell lymphoma to facilitate the early identification of the disease. METHODS: We retrospectively reviewed the brain MRI of biopsy-confirmed CNS B-cell lymphoma patients. They were initially diagnosed with CNS demyelination, and these images were compared with those of actual patients with demyelinating diseases. RESULTS: A total of 20 patients with CNS B-cell lymphoma and 12 patients with demyelination were included in this study. Cohesive enhancement with satellite enhancing foci surrounded by prominent non-enhancing areas of oedema is the major contrast-enhancing pattern of lymphoma patients, accounting for 81% (13) of patients with primary diffuse large B-cell lymphoma (DLBCL). This imaging pattern revealed a sensitivity of 81% and a specificity of 75% for lymphoma in the differential diagnosis between primary DLBCL and demyelinating disease in our cohort. Among these lesions, most of the nodules were located deeply, which yielded a specificity of 100% and a sensitivity of 69% for primary DLBCL. Enhancement in a single pattern (mainly ring-like, patchy or punctate; 57%) and no enhancement (30%) were commonly observed in demyelinating lesions, distinct from primary DLBCL (p < 0.05). CONCLUSIONS: Lesions with cohesive enhancement and satellite foci on T1 contrast-enhanced imaging could be a specific hallmark of CNS B-cell lymphoma, suggesting the need to withdraw steroidal therapy and biopsy confirmation.

Stereotactic biopsy for lesions in brainstem and deep brain: a single-center experience of 72 cases.

Stereotactic biopsies for lesions in the brainstem and deep brain are rare. This study aimed to summarize our 6-year experience in the accurate diagnosis of lesions in the brain stem and deep brain and to discuss the technical note and strategies. From December 2011 to January 2018, 72 cases of intracranial lesions in the brainstem or deep in the lobes undergoing stereotactic biopsy were retrospectively reviewed. An individualized puncture path was designed based on the lesion's location and the image characteristics. The most common biopsy targets were deep in the lobes (43 cases, 59.7%), including frontal lobe (33 cases, 45.8%), temporal lobe (4 cases, 5.6%), parietal lobe (3 cases, 4.2%), and occipital lobe (3 cases, 4.2 %). There were 12 cases (16.7%) of the brainstem, including 8 cases (11.1%) of midbrain, and 4 cases (5.6%) of pons or brachium pontis. Other targets included internal capsule (2 cases, 2.8%), thalamus (3 cases, 4.2%), and basal ganglion (12 cases, 16.7%). As for complications, one patient developed acute intracerebral hemorrhage in the biopsy area at 2 h post-operation, and one patient had delayed intracerebral hemorrhage at 7 days post-operation. The remaining patients recovered well after surgery. There was no surgery-related death. The CT-MRI-guided stereotactic biopsy of lesions in the brainstem or deep in the brain has the advantages of high safety, accurate diagnosis, and low incidence of complications. It plays a crucial role in the diagnosis of atypical, microscopic, diffuse, multiple, and refractory lesions.

High-salt diet downregulates TREM2 expression and blunts efferocytosis of macrophages after acute ischemic stroke.

BACKGROUND: A high-salt diet (HSD) is one of the major risk factors for acute ischemic stroke (AIS). As a potential mechanism, surplus salt intake primes macrophages towards a proinflammatory phenotype. In this study, whether HSD could blunt the efferocytic capability of macrophages after ischemic stroke, thus exacerbating post-stroke neural inflammation, was investigated. METHODS: Wild-type male C57BL/6 mice were fed with fodder containing 8% sodium chloride for 4 weeks and subjected to transient middle cerebral occlusion (tMCAO). Disease severity, macrophage polarization as well as efferocytic capability were evaluated. Bone marrow-derived macrophages were cultured in vitro, and the impact of high salinity on their efferocytic activity, as well as their expression of phagocytic molecules, were analyzed. The relationships among sodium concentration, macrophage phenotype, and disease severity in AIS patients were explored. RESULTS: HSD-fed mice displayed increased infarct volume and aggravated neurological deficiency. Mice fed with HSD suffered exacerbated neural inflammation as shown by higher inflammatory mediator expression and immune cell infiltration levels. Infiltrated macrophages within stroke lesions in HSD-fed mice exhibited a shift towards proinflammatory phenotype and impaired efferocytic capability. As assessed with a PCR array, the expression of triggering receptor expressed on myeloid cells 2 (TREM2), a receptor relevant to phagocytosis, was downregulated in high-salt-treated bone marrow-derived macrophages. Enhancement of TREM2 signaling restored the efferocytic capacity and cellular inflammation resolution of macrophages in a high salinity environment in vitro and in vivo. A high concentration of urine sodium in AIS patients was found to be correlated with lower TREM2 expression and detrimental stroke outcomes. CONCLUSIONS: HSD inhibited the efferocytic capacity of macrophages by downregulating TREM2 expression, thus impeding inflammation resolution after ischemic stroke. Enhancing TREM2 signaling in monocytes/macrophages could be a promising therapeutic strategy to enhance efferocytosis and promote post-stroke inflammation resolution.

Infiltration of plasma cells in colorectal adenocarcinoma associated with autoimmune encephalitis.

Paraneoplastic autoimmune encephalitis (PAE) represents a group of rare neurological syndromes associated with neoplastic diseases. Here, we report a case that multiple anti-neuronal antibodies were present in a patient with PAE who developed both small cell lung cancer and colorectal adenocarcinoma. Furthermore, the immunopathological investigation of the colorectal adenocarcinoma revealed the formation of abnormal neuronal antigens and a massive infiltration of plasma cells in the tumor tissue. These findings support the hypothesis that expression of neuronal antigens in neoplasm initiates autoimmune responses in PAE.

Stereotactic biopsy for lesions in brainstem and deep brain: a single-center experience of 72 cases

Stereotactic biopsies for lesions in the brainstem and deep brain are rare. This study aimed to summarize our 6-year experience in the accurate diagnosis of lesions in the brain stem and deep brain and to discuss the technical note and strategies. From December 2011 to January 2018, 72 cases of intracranial lesions in the brainstem or deep in the lobes undergoing stereotactic biopsy were retrospectively reviewed. An individualized puncture path was designed based on the lesion's location and the image characteristics. The most common biopsy targets were deep in the lobes (43 cases, 59.7%), including frontal lobe (33 cases, 45.8%), temporal lobe (4 cases, 5.6%), parietal lobe (3 cases, 4.2%), and occipital lobe (3 cases, 4.2 %). There were 12 cases (16.7%) of the brainstem, including 8 cases (11.1%) of midbrain, and 4 cases (5.6%) of pons or brachium pontis. Other targets included internal capsule (2 cases, 2.8%), thalamus (3 cases, 4.2%), and basal ganglion (12 cases, 16.7%). As for complications, one patient developed acute intracerebral hemorrhage in the biopsy area at 2 h post-operation, and one patient had delayed intracerebral hemorrhage at 7 days post-operation. The remaining patients recovered well after surgery. There was no surgery-related death. The CT-MRI-guided stereotactic biopsy of lesions in the brainstem or deep in the brain has the advantages of high safety, accurate diagnosis, and low incidence of complications. It plays a crucial role in the diagnosis of atypical, microscopic, diffuse, multiple, and refractory lesions.

Germinomas of the basal ganglia and thalamus: Four case reports.

BACKGROUND: The early diagnosis of basal ganglia and thalamus germinomas is often difficult due to the absence of elevated tumor markers, and atypical clinical symptoms and neuroimaging features. CASE SUMMARY: Four male children aged 8 to 15 years were diagnosed with germinomas in the basal ganglia and thalamus by stereotactic biopsy from 2017 to 2019. All patients developed hemiplegia except patient 4 who also had cognitive decline, speech disturbance, nocturnal enuresis, polydipsia, polyuria, precocious puberty and abnormalities of thermoregulation. All four cases were alpha-fetoprotein and beta-human chorionic gonadotrophin (ß-HCG) negative except patient 3 who had slightly elevated ß-HCG in cerebrospinal fluid (CSF). No malignant cells were detected in the patients' CSF. Brain magnetic resonance imaging findings were diverse in these patients with the exception of the unique and common characteristics of ipsilateral hemisphere atrophy, especially in the cerebral peduncle. All patients were diagnosed with germinomas of the basal ganglia and thalamus by stereotactic brain biopsy. CONCLUSION: Stereotactic brain biopsy is necessary to confirm the diagnosis of ectopic germinomas. Serial neuroimaging studies can not only differentiate disease but also determine the biopsy site.

Astrocyte-derived VEGF increases cerebral microvascular permeability under high salt conditions.

Excess salt (NaCl) intake is closely related to a variety of central nervous system (CNS) diseases characterized by increased cerebral microvascular permeability. However, the link between a high salt diet (HSD) and the breakdown of tight junctions (TJs) remains unclear. In the present study, we found that high salt does not directly influence the barrier between endothelial cells, but it suppresses expression of TJ proteins when endothelial cells are co-cultured with astrocytes. This effect is independent of blood pressure, but depends on the astrocyte activation via the NFκB/MMP-9 signaling pathway, resulting in a marked increase in VEGF expression. VEGF, in turn, induces disruption of TJs by inducing phosphorylation and activation of ERK and eNOS. Correspondingly, the HSD-induced disruption of TJ proteins is attenuated by blocking VEGF using the specific monoclonal antibody Bevacizumab. These results reveal a new axis linking a HSD to increased cerebral microvascular permeability through a VEGF-initiated inflammatory response, which may be a potential target for preventing the deleterious effects of HSD on the CNS.

Chronic Insomnia Is Associated with Higher Circulating Interleukin-8 in Patients with Atherosclerotic Cerebral Small Vessel Disease.

OBJECTIVE: Chronic inflammatory responses and leukocyte infiltration are classical pathological features of cerebral small vessel disease (CSVD). To date, limited evidence of a relationship between chronic insomnia and inflammatory responses in patients with CSVD has been uncovered. The purpose of the present study was to investigate the potential relationship between chronic insomnia and pro-inflammatory cytokine levels in patients with atherosclerotic CSVD (A-CSVD). METHODS: In total, 76 A-CSVD patients with or without chronic insomnia (CI) confirmed using magnetic resonance (MR) were prospectively recruited. Overnight polysomnography (PSG) was performed and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-6, IL-17A, IL-8, and IL-12 assessed. Cytokine levels were compared between CSVD+CI (study group) and CSVD without CI (control group) patients, and the correlations between PSG parameters and cytokine levels were explored in all patients via multiple linear regression analyses. RESULTS: The serum IL-8 level of the study group (12.3±4.4 pg/mL) was significantly higher than that of the control group (7.5±2.2 pg/mL; P<0.05). PSG measurements showed that patients in the study group had significantly higher sleep onset latency (SOL), arousal index (ArI) and wake after sleep onset (WASO) as well as lower total sleep time (TST), sleep efficiency (SE) and stage 3 NREM sleep (N-3) ratio, compared with the control group (P<0.05). Multiple linear regression analyses led to the identification of ArI (ß=0.026, P<0.05) and TST (ß=-0.054, P<0.05) as significant positive and negative predictors of the IL-8 level, respectively. CONCLUSION: Chronic insomnia, in particular, sleep fragmentation and short sleep duration, may be involved in promotion of serum IL-8 expression in patients with atherosclerotic CSVD.

Update of inflammasome activation in microglia/macrophage in aging and aging-related disease.

Aging and aging-related CNS diseases are associated with inflammatory status. As an efficient amplifier of immune responses, inflammasome is activated and played detrimental role in aging and aging-related CNS diseases. Macrophage and microglia display robust inflammasome activation in infectious and sterile inflammation. This review discussed the impact of inflammasome activation in microglia/macrophage on senescence "inflammaging" and aging-related CNS diseases. The preventive or therapeutic effects of targeting inflammasome on retarding aging process or tackling aging-related diseases are also discussed.

The glucagon-like peptide-1 receptor agonist reduces inflammation and blood-brain barrier breakdown in an astrocyte-dependent manner in experimental stroke.

BACKGROUND: Preserving the integrity of the blood-brain barrier (BBB) is beneficial to avoid further brain damage after acute ischemic stroke (AIS). Astrocytes, an important component of the BBB, promote BBB breakdown in subjects with AIS by secreting inflammatory factors. The glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 (Ex-4) protects the BBB and reduces brain inflammation from cerebral ischemia, and GLP-1R is expressed on astrocytes. However, the effect of Ex-4 on astrocytes in subjects with AIS remains unclear. METHODS: In the present study, we investigated the effect of Ex-4 on astrocytes cultured under oxygen-glucose deprivation (OGD) plus reoxygenation conditions and determined whether the effect influences bEnd.3 cells. We used various methods, including permeability assays, western blotting, immunofluorescence staining, and gelatin zymography, in vitro and in vivo. RESULTS: Ex-4 reduced OGD-induced astrocyte-derived vascular endothelial growth factor (VEGF-A), matrix metalloproteinase-9 (MMP-9), chemokine monocyte chemoattractant protein-1 (MCP-1), and chemokine C-X-C motif ligand 1 (CXCL-1). The reduction in astrocyte-derived VEGF-A and MMP-9 was related to the increased expression of tight junction proteins (TJPs) in bEnd.3 cells. Ex-4 improved neurologic deficit scores, reduced the infarct area, and ameliorated BBB breakdown as well as decreased astrocyte-derived VEGF-A, MMP-9, CXCL-1, and MCP-1 levels in ischemic brain tissues from rats subjected to middle cerebral artery occlusion. Ex-4 reduced the activation of the JAK2/STAT3 signaling pathway in astrocytes following OGD. CONCLUSION: Based on these findings, ischemia-induced inflammation and BBB breakdown can be improved by Ex-4 through an astrocyte-dependent manner.