896 research outputs found
Disruption of embryonic blood-CSF barrier in chick embryos reveals the actual importance of this barrier to control E-CSF composition and homeostasis in early brain development
No full textIn vertebrates, early brain development takes place at the expanded anterior end of the neural tube. After closure of the anterior neuropore, the brain wall forms a physiologically sealed cavity that encloses embryonic cerebrospinal fluid (E-CSF), a complex and protein-rich fluid that is initially composed of trapped amniotic fluid. E-CSF has several crucial roles in brain anlagen development. Recently, we reported the presence of transient blood-CSF barrier located in the brain stem lateral to the ventral midline, at the mesencephalon and prosencephalon level, in chick and rat embryos by transporting proteins, water, ions and glucose in a selective manner via transcellular routes. To test the actual relevance of the control of E-CSF composition and homeostasis on early brain development by this embryonic blood-CSF barrier, we block the activity of this barrier by treating the embryos with 6-aminonicotinamide gliotoxin (6-AN). We demonstrate that 6-AN treatment in chick embryos blocks protein transport across the embryonic blood-CSF barrier, and that the disruption of the barrier properties is due to the cease transcellular caveolae transport, as detected by CAV-1 expression cease. We also show that the lack of protein transport across the embryonic blood-CSF barrier influences neuroepithelial cell survival, proliferation and neurogenesis, as monitored by neurepithelial progenitor cells survival, proliferation and neurogenesis. The blockage of embryonic blood-CSF transport also disrupts water influx to the E-CSF, as revealed by an abnormal increase in brain anlagen volume. These experiments contribute to delineate the actual extent of this blood-CSF embryonic barrier controlling E-CSF composition and homeostasis and the actual important of this control for early brain development, as well as to elucidate the mechanism by which proteins and water are transported thought transcellular routes across the neuroectoderm, reinforcing the crucial role of E-CSF for brain development
M-CSF and GM-CSF influence naïve murine alveolar macrophage differentiation and function in vitro
No full textThis research has been published in Relative Levels of M-CSF and GM-CSF Influence the Specific Generation of Macrophage Populations during Infection with Mycobacterium tuberculosis by Higgins, D et al. in Journal of Immunology, 2008, 180: 4892-4900.The objective of this study was to compare the effect of M-CSF and GM-CSF in their abilities to affect the functional and phenotypical characteristics of AMs. In this study, we harvested naïve uninfected murine alveolar macrophages by bronchoalveolar lavage (BAL) and cultured in the presence of M-CSF, GM-CSF or both. GM-CSF stimulated cell proliferation at a higher rate when measured by relative loss of CFDA-SE dye and had higher phagocytic capacity than M-CSF cultured cells. In contrast, alveolar macrophages cultured in the presence of M-CSF exhibited a dendritic-cell-like morphology and upregulated expression of dendriticcell- associated markers like CCR7, MHC II and DEC205. The dendritic cell character of M-CSF-treated AMs was also manifested in their higher capacity to stimulate CD4+ T cell proliferation in a mixed lymphocyte reaction (MLR). This study demonstrates that M-CSF has a strong ability to differentiate AMs into DC-like cells.Highest Honors
Loss of GM-CSF-dependent instruction of alveolar macrophages in COVID-19 provides a rationale for inhaled GM-CSF treatment
No full textGM-CSF promotes myelopoiesis and inflammation, and GM-CSF blockade is being evaluated as a treatment for COVID-19-associated hyperinflammation. Alveolar GM-CSF is, however, required for monocytes to differentiate into alveolar macrophages (AMs) that control alveolar homeostasis. By mapping cross-species AM development to clinical lung samples, we discovered that COVID-19 is marked by defective GM-CSF-dependent AM instruction and accumulation of pro-inflammatory macrophages. In a multi-center, open-label RCT in 81 non-ventilated COVID-19 patients with respiratory failure, we found that inhalation of rhu-GM-CSF did not improve mean oxygenation parameters compared with standard treatment. However, more patients on GM-CSF had a clinical response, and GM-CSF inhalation induced higher numbers of virus-specific CD8 effector lymphocytes and class-switched B cells, without exacerbating systemic hyperinflammation. This translational proof-of-concept study provides a rationale for further testing of inhaled GM-CSF as a non-invasive treatment to improve alveolar gas exchange and simultaneously boost antiviral immunity in COVID-19. This study is registered at ClinicalTrials.gov (NCT04326920) and EudraCT (2020-001254-22)
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Understanding 1968: the case of Brest
No full textThis article examines the dominance of Paris in how May '68 has been portrayed over the years. It will be argued, through a case-study of the revolt in the Breton city of Brest, that the Paris-centred approach is one that belies the true nationwide aspect of May/June 1968. As one of a range of characteristics, the concentration on the Latin Quarter has helped mould what Kristin Ross has described as the 'official history' of 1968. An examination of how the events were played out within different regional contexts would go a long way towards helping overcome the shortcomings of the increasingly narrow portrayal that has come to dominate the stereotypical image of 1968
Quantitative proteome responses to oncolytic reovirus in GM-CSF- and M-CSF-differentiated bone marrow-derived cells
No full textThe efficacy of oncolytic viruses (OVs), such as reovirus, is dictated by host immune responses, including those mediated by the pro- versus anti-inflammatory macrophages. As such, a detailed understanding of the interaction between reovirus and different macrophage types is critical for therapeutic efficacy. To explore reovirus–macrophage interactions, we performed tandem mass tag (TMT)-based quantitative temporal proteomics on mouse bone marrow-derived macrophages (BMMs) generated with two cytokines, macrophage colony stimulating factor (M-CSF) and granulocytic–macrophage colony stimulating factor (GM-CSF), representing anti- and proinflammatory macrophages, respectively. We quantified 6863 proteins across five time points in duplicate, comparing M-CSF (M-BMM) and GM-CSF (GM-BMM) in response to OV. We find that GM-BMMs have lower expression of key intrinsic proteins that facilitate an antiviral immune response, express higher levels of reovirus receptor protein JAM-A, and are more susceptible to oncolytic reovirus infection compared to M-BMMs. Interestingly, although M-BMMs are less susceptible to reovirus infection and subsequent cell death, they initiate an antireovirus adaptive T cell immune response comparable to that of GM-BMMs. Taken together, these data describe distinct proteome differences between these two macrophage populations in terms of their ability to mount antiviral immune responses.Canadian Cancer Society Research InstituteCanadian Institutes of Health ResearchTerry Fox Research InstituteQEII Health Sciences Centre Foundatio
Preconditioning Triggered by Carbon Monoxide (CO) Provides Neuronal Protection Following Perinatal Hypoxia-Ischemia
No full textPerinatal hypoxia-ischemia is a major cause of acute mortality in newborns and cognitive and motor impairments in children. Cerebral hypoxia-ischemia leads to excitotoxicity and necrotic and apoptotic cell death, in which mitochondria play a major role. Increased resistance against major damage can be achieved by preconditioning triggered by subtle insults. CO, a toxic molecule that is also generated endogenously, may have a role in preconditioning as low doses can protect against inflammation and apoptosis. In this study, the role of CO-induced preconditioning on neurons was addressed in vitro and in vivo. The effect of 1 h of CO treatment on neuronal death (plasmatic membrane permeabilization and chromatin condensation) and bcl-2 expression was studied in cerebellar granule cells undergoing to glutamate-induced apoptosis. CO's role was studied in vivo in the Rice-Vannucci model of neonatal hypoxia-ischemia (common carotid artery ligature +75 min at 8% oxygen). Apoptotic cells, assessed by Nissl staining were counted with a stereological approach and cleaved caspase 3-positive profiles in the hippocampus were assessed. Apoptotic hallmarks were analyzed in hippocampal extracts by Western Blot. CO inhibited excitotoxicity-induced cell death and increased Bcl-2 mRNA in primary cultures of neurons. In vivo, CO prevented hypoxia-ischemia induced apoptosis in the hippocampus, limited cytochrome c released from mitochondria and reduced activation of caspase-3. Still, Bcl-2 protein levels were higher in hippocampus of CO pre-treated rat pups. Our results show that CO preconditioning elicits a molecular cascade that limits neuronal apoptosis. This could represent an innovative therapeutic strategy for high-risk cerebral hypoxia-ischemia patients, in particular neonates.© Queiroga et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
Effects of age and glucose on lactate in CSF
No full textDespite recent studies examining the association between neurodegenerative diseases and mitochondrial dysfunction, there are not sufficient data on factors that influence cerebrospinal fluid (CSF) lactate levels. Thus, we investigated factors that affect CSF lactate levels in neurodegenerative diseases. We extracted laboratory findings, including CSF lactate, glucose, and protein levels, and demographic and background information, including age and gender, from the electronic medical records of patients with neurodegenerative diseases in order to explore factors that have an impact CSF lactate levels. These patients had been admitted to our department and underwent a CSF examination between April 2007 and March 2015. Data from 83 patients (average age 64.5 years; 45 males and 38 females) were analyzed. The patients' diagnoses included amyotrophic lateral sclerosis, multiple system atrophy, spinocerebellar degeneration, corticobasal syndrome, Parkinson's disease, and Huntington's disease. CSF lactate levels were higher in patients with a neurodegenerative disease who were aged 65 years and older relative to those who were aged under 65 years (p < 0.05), and CSF lactate and glucose levels showed a moderate positive correlation (r = 0.487). Age and CSF glucose levels influenced CSF lactate levels even after adjusting for gender, age, CSF protein levels, and CSF glucose levels. When investigating CSF lactate levels in neurodegenerative diseases, it is necessary to consider patients' age and CSF glucose levels
Differentiation and activation of functionally distinct macrophage populations by CSF-1 and GM-CSF
No full textMacrophages derived in vitro from bone marrow progenitor cells (BMDM) under the influence of CSF-1 or GM-CSF were compared for immune function. CSF-1- and GM-CSF-derived BMDM did not differ in their ability to kill L929 tumor targets or produce IL-6 and LTC\sb4 in response to IFN- and LPS. CSF-1-derived BMDM secreted more TNF- and PGE\sb2 at early stages of culture than did GM-CSF-derived BMDM and required only LPS stimulation to produce NO\sb2\sp-. In contrast, GM-CSF-derived BMDM secreted NO\sb2\sp- only following treatment with IFN- plus LPS. When P815 tumor targets were used, GM-CSF-derived BMDM displayed higher basal and inducible levels of killing than CSF-1-derived BMDM and required only LPS treatment to reach full cytolytic capacity. Additionally, GM-CSF-derived BMDM showed greater listeriacidal capacity than did CSF-1-derived BMDM, particularly following IFN- plus LPS treatment. To assess immunocompetence under conditions resembling those of inflammatory sites, BMDM function was examined following treatment with PGE\sb2 or in conditions of reduced L-arginine concentration. PGE\sb2 (10\sp{-6}-10\sp{-8} M) had no effect on BMDM ability to cytolyze L929 cells, kill intracellular Listeria, or produce NO\sb2\sp-, but GM-CSF-derived BMDM were inhibited 33% for cytolysis of K562 tumor cells. Interestingly, GM-CSF-derived BMDM were much less sensitive than CSF-1-derived BMDM for PGE\sb2, but not cAMP-mediated inhibition of TNF-. Arginine depletion blocked NO\sb2\sp- production by both BMDM populations and the listeriacidal activity induced by IFN- plus LPS was abolished.Macrophages were elicited in CB-17 and scid mice by repeated injection of GM-CSF. Following challenge with Listeria, scid mice which had been pretreated with GM-CSF showed reduced numbers of bacteria in the liver and spleens. CB-17 mice were unaffected by GM-CSF administration.When used alone, neither CSF-1 nor GM-CSF elicited TNF-, NO\sb2\sp-, or PGE\sb2 secretion. GM-CSF primed CSF-1-derived BMDM for enhanced LPS-induced TNF-, NO\sb2\sp-, and PGE\sb2 secretion, and for augmented cytolysis of P815, but not K562 tumor cells. Thus, GM-CSF elicits a macrophage population with functional signal requirements distinct from those of CSF-1-derived BMDM and is a more effective biological response modifier for macrophage function than is CSF-1.Made available in DSpace on 2011-05-07T12:35:11Z (GMT). No. of bitstreams: 2
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[[alternative]]Effects of G-CSF on neuropathic pain of rats with chronic constriction
No full text[[abstract]]Neuropathic pain is due to long-term dysfunction of the nervous system and is difficult to managements and treatments. Under inflammatory conditions, leukocytes secrete opioid peptides, which bind to opioid receptors on peripheral sensory neurons and mediate antinociception. The majority of opioid-containing leukocytes are PMN during early inflammation. Granulocyte-colony stimulating factor (G-CSF) is a particular growth factor that works by encouraging the bone marrow to produce more stem cells which then differentiate into white blood cells, especially the PMN. Therefore, G-CSF has a potential to become an anti-nociceptive agent. In the study we use chronic constriction injury model to produce neuropathic pain in rats with nerve injury. Thereafter, we performed behavior tests including thermal and mechanical responses. Our results indicated the experimental group with i.v. G-CSF showed less severe neuropathic pain than control with normal saline within 2 days post-operation. In flow cytometry and immuno-histochemical studies the numbers of PMN cells around sciatic nerve in the group with G-CSF treatment showed much more than the control group. The results demonstrated the effects of G-CSF on neuropathic pain are probably through the opioid compounds secreted by PMN cells. Besides, we find that G-CSF maybe inhabit the expression of several proinflammatory cytokine, like IL-1β and IL-6 by SQ-RT-PCR. So the mechanism of G-CSF to save pain may not only due to the opioid compound secreted by PMN cells but inhabit the expression of IL-1βand IL-6 to suppress the inflammatory and neuropathic pain.
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