Similar Datasets
Project description:Disturbances in the glutamatergic system have been linked to neuronal pathology. Investigating therapeutic translation, we discovered immune-related effects for the selective non-competitive AMPA receptor blocker perampanel in mouse models of multiple sclerosis.
2025-06-13 | GSE249327 | GEO
Project description:Disturbances in the glutamatergic system have been linked to neuronal pathology. Investigating therapeutic translation, we discovered immune-related effects for the selective non-competitive AMPA receptor blocker perampanel in mouse models of multiple sclerosis.
2025-06-13 | GSE249326 | GEO
Project description:Non-canonical AMPA receptor blockade reduces lymph node egress and neuroinflammation
| PRJNA1048528 | ENA
Project description:Non-canonical AMPA receptor blockade reduces lymph node egress and neuroinflammation [scRNA-seq]
| PRJNA1048531 | ENA
Project description:Non-canonical AMPA receptor blockade reduces lymph node egress and neuroinflammation [Bulk RNA-seq]
| PRJNA1048526 | ENA
Project description:Dyslipidemia is a central component of atherosclerosis and metabolic syndrome linked to chronic inflammation and immune dysfunction. Previously, we showed that hypercholesterolemic apolipoprotein E knock out (apoE-/-) mice exhibit systemic effects including skin inflammation and hypertrophic lymph nodes (LNs). However, the mechanisms accounting for LN hypertrophy in these mice remain unknown. Here, we show that hypercholesterolemia led to the accumulation of lymphocytes in LNs. We excluded that the increased number of lymphocytes in expanded LNs resulted from increased lymphocyte proliferation or entry into those LNs. Instead, we demonstrated that the egress of lymphocytes from the enlarged LN of apoE-/- mice was markedly decreased. Impairment in efferent lymphatic emigration of lymphocytes from LNs resulted from an aberrant expansion of cortical and medullary sinuses that became hyperplastic. Moreover, CCL21 was more abundant on these enlarged sinuses whereas lymph levels of sphingosine 1 phosphate (S1P) were decreased in apoE-/- mice. Normal LN size, lymphatic density and S1P levels were restored by reversing hypercholesterolemia. Thus, systemic changes in cholesterol can sequester lymphocytes in tissue draining LNs through the extensive remodeling of lymphatic sinuses and alteration of the balance between retention/egress signals leading to LN hypertrophy which subsequently may contribute to poor immunity. This study further illustrates the role of lymphatic vessels in immunity through the regulation of immune cell trafficking.
| S-EPMC6446103 | biostudies-literature
Project description:Allergic asthma is mediated by Th2 responses to inhaled allergens. Although previous experiments indicated that Notch signaling activates expression of the key Th2 transcription factor Gata3, it remains controversial how Notch promotes allergic airway inflammation. Here we show that T cell-specific Notch deficiency in mice prevented house dust mite-driven eosinophilic airway inflammation and significantly reduced Th2 cytokine production, serum IgE levels, and airway hyperreactivity. However, transgenic Gata3 overexpression in Notch-deficient T cells only partially rescued this phenotype. We found that Notch signaling was not required for T cell proliferation or Th2 polarization. Instead, Notch-deficient in vitro-polarized Th2 cells showed reduced accumulation in the lungs upon in vivo transfer and allergen challenge, as Notch-deficient Th2 cells were retained in the lung-draining lymph nodes. Transcriptome analyses and sequential adoptive transfer experiments revealed that while Notch-deficient lymph node Th2 cells established competence for lung migration, they failed to upregulate sphingosine-1-phosphate receptor 1 (S1PR1) and its critical upstream transcriptional activator Krüppel-like factor 2 (KLF2). As this KLF2/S1PR1 axis represents the essential cell-intrinsic regulator of T cell lymph node egress, we conclude that the druggable Notch signaling pathway licenses the Th2 response in allergic airway inflammation via promoting lymph node egress.
| S-EPMC7324208 | biostudies-literature
Project description:Recent studies have identified cortical sinuses as sites of sphingosine-1-phosphate receptor-1 (S1P(1))-dependent T- and B-cell egress from the lymph node (LN) parenchyma. However, the distribution of cortical sinuses in the entire LN and the extent of lymph flow within them has been unclear. Using 3D reconstruction and intravital two-photon microscopy we describe the branched organization of the cortical sinus network within the inguinal LN and show that lymphocyte flow begins within blunt-ended sinuses. Many cortical sinuses are situated adjacent to high endothelial venules, and some lymphocytes access these sinuses within minutes of entering a LN. However, upon entry to inflamed LNs, lymphocytes rapidly up-regulate CD69 and are prevented from accessing cortical sinuses. Using the LN reconstruction data and knowledge of lymphocyte migration and cortical sinus entry dynamics, we developed a mathematical model of T-cell egress from LNs. The model suggests that random walk encounters with lymphatic sinuses are the major factor contributing to LN transit times. A slight discrepancy between predictions of the model and the measured transit times may be explained by lymphocytes undergoing a few rounds of migration between the parenchyma and sinuses before departing from the LN. Because large soluble antigens gain rapid access to cortical sinuses, such parenchyma-sinus shuttling may facilitate antibody responses.
| S-EPMC2996652 | biostudies-literature
Project description:Cocaine use disorder is a major health crisis that is associated with increased oxidative stress and neuroinflammation. While the role of NLRP3 inflammasome in mediating neuroinflammation is well-recognized, whether cocaine induces this response remains unexplored. Based on the premise that cocaine induces both reactive oxygen species (ROS) as well as microglial activation, we hypothesized that cocaine-mediated microglial activation involves both ROS and NLRP3 signaling pathways. We examined activation of the NLRP3 pathway in microglia exposed to cocaine, followed by validation in mice administered either cocaine or saline for 7 days, with or without pretreatment with the NLRP3 inhibitor, MCC950, and in postmortem cortical brain tissues of chronic cocaine-dependent humans. We found that microglia exposed to cocaine exhibited significant induction of NLRP3 and mature IL-1β expression. Intriguingly, blockade of ROS (Tempol) attenuated cocaine-mediated priming of NLRP3 and microglial activation (CD11b). Blockade of NLRP3 by both pharmacological (MCC950) as well as gene silencing (siNLRP3) approaches underpinned the critical role of NLRP3 in cocaine-mediated activation of inflammasome and microglial activation. Pretreatment of mice with MCC950 followed by cocaine administration for 7 days mitigated cocaine-mediated upregulation of mature IL-1β and CD11b, in both the striatum and the cortical regions. Furthermore, cortical brain tissues of chronic cocaine-dependent humans also exhibited upregulated expression of the NLRP3 pathway mediators compared with non-cocaine dependent controls. Collectively, these findings suggest that cocaine activates microglia involving the NLRP3 inflammasome pathway, thereby contributing to neuroinflammation. NLRP3 can thus be considered as a potential therapeutic target for alleviating cocaine-mediated neuroinflammation.
| S-EPMC8026688 | biostudies-literature
Project description:BackgroundThe incidence of lymph node metastases is closely related to the T-stage, and therefore Eastern guidelines advice a D1 lymphadenectomy for early gastric cancer and a D2 lymphadenectomy for advanced gastric cancer. The aim of this study was to compare the lymph node metastases rate in the stations dissected with a D2-lymphadenectomy (stations 8-12) yet spared with a D1-lymphadenectomy, between different T-stages in a Western patient cohort.MethodsFor this retrospective study, patients who underwent a gastrectomy in the Amsterdam University Medical Center (UMC), location Academic Medical Center (AMC), between 2011 and 2016 were identified from a prospectively maintained database. The primary outcome was to compare the rate of lymph node metastases in station 8-12 between different cT-stages.ResultsOne hundred twelve patients met our inclusion criteria. There were no positive lymph nodes in the lymph nodes stations 8-12 in cT1 and (y)pT1-stage tumors. The more advanced cT2-4 and (y)pT2-4 stage tumors show a high metastases rate (11.1% to 40.0%) in the lymph node stations 8-12.ConclusionsThe results from this study endorse the Japanese Gastric Cancer Guideline; in early gastric cancer, a D1 lymphadenectomy is sufficient, while in advanced gastric cancer a D2 lymphadenectomy should be performed.
| S-EPMC9459217 | biostudies-literature