scholarly journals Activation of Proinflammatory Caspases by Cathepsin B in Focal Cerebral Ischemia

2004 ◽  
Vol 24 (11) ◽  
pp. 1272-1279 ◽  
Author(s):  
Alexandra Benchoua ◽  
Jérôme Braudeau ◽  
Aurélia Reis ◽  
Cécile Couriaud ◽  
Brigitte Onténiente
Keyword(s):  
Cell Death ◽  
Cathepsin B ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Critical Role ◽  
Early Event ◽  
Ischemic Damage ◽  
Activation Pattern ◽  
Infarct Core

Cathepsins and caspases are two families of proteases that play pivotal roles in ischemic cell death. This study investigated the existence of a cross-talk between cathepsin B and proinflammatory caspases in stroke-induced cell death, as recently suggested by in vitro data. Cortical ischemic damage was induced in mice by distal and permanent occlusion of the middle cerebral artery. Cytoplasmic activation of cathepsin B was observed from the early stages of infarction, and displayed an activation pattern parallel to the activation pattern of caspase-1 and −11. Immunohistochemistry revealed the colocalization of cathepsin B with each caspase in cells of the infarct core. The apical position of cathepsin B in both caspase-activation cascades was confirmed by pretreatment of the animals with the cathepsin B inhibitor CA-074, which also potently protected cortical structures from ischemic damage, indicating involvement of the proteases in the lesion process. The results show that cathepsin B release is an early event following occlusion of cerebral arteries, which eventually triggers the activation of proinflammatory caspases in the absence of reperfusion. This new pathway may play a critical role in brain infarction by promoting inflammatory responses, and/or by amplifying the apoptotic process.

scholarly journals Neuroinflammation Extends Brain Tissue at Risk to Vital Peri-Infarct Tissue: A Double Tracer [11C]PK11195- and [18F]FDG-PET Study

2009 ◽  
Vol 29 (6) ◽  
pp. 1216-1225 ◽  
Author(s):  
Michael Schroeter ◽  
Maria A Dennin ◽  
Maureen Walberer ◽  
Heiko Backes ◽  
Bernd Neumaier ◽  
...  
Keyword(s):  
At Risk ◽  
Cerebral Ischemia ◽  
Fdg Pet ◽  
Energy Demand ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Benzodiazepine Receptors ◽  
Transient Ischemia ◽  
Infarct Core ◽  
Infarct Zone

Focal cerebral ischemia elicits strong inflammatory responses involving activation of resident microglia and recruitment of monocytes/macrophages. These cells express peripheral benzodiazepine receptors (PBRs) and can be visualized by positron emission tomography (PET) using [11C]PK11195 that selectively binds to PBRs. Earlier research suggests that transient ischemia in rats induces increased [11C]PK11195 binding within the infarct core. In this study, we investigated the expression of PBRs during permanent ischemia in rats. Permanent cerebral ischemia was induced by injection of macrospheres into the middle cerebral artery. Multimodal imaging 7 days after ischemia comprised (1) magnetic resonance imaging that assessed the extent of infarcts; (2) [18F]-2-fluoro-2-deoxy-d-glucose ([18F]FDG)-PET characterizing cerebral glucose transport and metabolism; and (3) [11C]PK11195-PET detecting neuroinflammation. Immunohistochemistry verified ischemic damage and neuroinflammatory processes. Contrasting with earlier data for transient ischemia, no [11C]PK11195 binding was found in the infarct core. Rather, permanent ischemia caused increased [11C]PK11195 binding in the normoperfused peri-infarct zone (mean standard uptake value (SUV): 1.93 ± 0.49), colocalizing with a 60% increase in the [18F]FDG metabolic rate constant with accumulated activated microglia and macrophages. These results suggest that after permanent focal ischemia, neuroinflammation occurring in the normoperfused peri-infarct zone goes along with increased energy demand, therefore extending the tissue at risk to areas adjacent to the infarct.

scholarly journals Genetic targeting of Card19 is linked to disrupted NINJ1 expression, impaired cell lysis, and increased susceptibility to Yersinia infection

2021 ◽  
Vol 17 (10) ◽  
pp. e1009967
Author(s):  
Elisabet Bjanes ◽  
Reyna Garcia Sillas ◽  
Rina Matsuda ◽  
Benjamin Demarco ◽  
Timothée Fettrelet ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membrane ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Lysis ◽  
Terminal Cell ◽  
Caspase Activation ◽  
Membrane Rupture ◽  
Genetic Targeting ◽  
Increased Susceptibility

Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1β release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during Yersinia infection, we identified a line of Card19-deficient mice (Card19lxcn) whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as an independently-generated CRISPR/Cas9 Card19 knockout mouse line (Card19Null) showed no defect in macrophage cell lysis. Notably, Card19 is located on chromosome 13, immediately adjacent to Ninj1, which was recently found to regulate cell lysis downstream of GSDMD activation. RNA-seq and western blotting revealed that Card19lxcn BMDMs have significantly reduced NINJ1 expression, and reconstitution of Ninj1 in Card19lxcn immortalized BMDMs restored their ability to undergo cell lysis in response to caspase-dependent cell death stimuli. Card19lxcn mice exhibited increased susceptibility to Yersinia infection, whereas independently-generated Card19Null mice did not, demonstrating that cell lysis itself plays a key role in protection against bacterial infection, and that the increased infection susceptibility of Card19lxcn mice is attributable to loss of NINJ1. Our findings identify genetic targeting of Card19 being responsible for off-target effects on the adjacent gene Ninj1, disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during Yersinia infection.

scholarly journals Brain-to-cervical lymph node signaling after stroke

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Elga Esposito ◽  
Bum Ju Ahn ◽  
Jingfei Shi ◽  
Yoshihiko Nakamura ◽  
Ji Hyun Park ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Lymph Node ◽  
Cerebral Ischemia ◽  
Systemic Inflammation ◽  
Cervical Lymph Node ◽  
Inflammatory Responses ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Surgical Removal ◽  
Lymphatic Endothelial Cells

AbstractAfter stroke, peripheral immune cells are activated and these systemic responses may amplify brain damage, but how the injured brain sends out signals to trigger systemic inflammation remains unclear. Here we show that a brain-to-cervical lymph node (CLN) pathway is involved. In rats subjected to focal cerebral ischemia, lymphatic endothelial cells proliferate and macrophages are rapidly activated in CLNs within 24 h, in part via VEGF-C/VEGFR3 signalling. Microarray analyses of isolated lymphatic endothelium from CLNs of ischemic mice confirm the activation of transmembrane tyrosine kinase pathways. Blockade of VEGFR3 reduces lymphatic endothelial activation, decreases pro-inflammatory macrophages, and reduces brain infarction. In vitro, VEGF-C/VEGFR3 signalling in lymphatic endothelial cells enhances inflammatory responses in co-cultured macrophages. Lastly, surgical removal of CLNs in mice significantly reduces infarction after focal cerebral ischemia. These findings suggest that modulating the brain-to-CLN pathway may offer therapeutic opportunities to ameliorate systemic inflammation and brain injury after stroke.

scholarly journals Osteopontin Augments M2 Microglia Response and Separates M1- and M2-Polarized Microglial Activation in Permanent Focal Cerebral Ischemia

2017 ◽  
Vol 2017 ◽  
pp. 1-11 ◽  
Author(s):  
Anne Ladwig ◽  
Helene Luise Walter ◽  
Jörg Hucklenbroich ◽  
Antje Willuweit ◽  
Karl-Josef Langen ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Infarct Core ◽  
M2 Microglia ◽  
Photothrombotic Stroke ◽  
M2 Phenotype

Background.Focal cerebral ischemia induces distinct neuroinflammatory processes. We recently reported the extracellular phosphor-glyco-protein osteopontin (OPN) to directly affect primary microgliain vitro, promoting survival while shifting their inflammatory profile towards a more neutral phenotype. We here assessed the effects of OPN on microglia after strokein vivo, with focus on infarct demarcation.Methods.Animals underwent focal photothrombotic stroke and were injected intracerebroventricularly with 500 μg OPN or vehicle. Immunohistochemistry assessed neuronal damage and infarct volume, neovascularisation, glial scar formation, microglial activation, and M1 and M2 polarisation.Results.After photothrombotic stroke, areas covered by M1 and M2 microglia substantially overlapped. OPN treatment reduced that overlap, with microglia appearing more spread out and additionally covering the infarct core. OPN additionally modulated the quantity of microglia subpopulations, reducing iNOS+ M1 cells while increasing M2 microglia, shifting the M1/M2 balance towards an M2 phenotype. Moreover, OPN polarized astrocytes towards the infarct.Conclusion.Microglial activation and M1 and M2 polarization have distinct but overlapping spatial patterns in permanent focal ischemia. Data suggest that OPN is involved in separating M1 and M2 subpopulations, as well as in shifting microglia polarization towards the M2 phenotype modulating beneficially inflammatory responses after focal infarction.

Granulocyte apoptosis: who would work with a ‘real’ inflammatory cell?

2004 ◽  
Vol 32 (3) ◽  
pp. 447-451 ◽  
Author(s):  
I. Dransfield ◽  
A.G. Rossi
Keyword(s):  
Cell Death ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Cell Types ◽  
Neutrophil Granulocyte ◽  
New Therapeutic Approaches ◽  
Key Factor ◽  
Potential Benefits ◽  
Innate Defence

The neutrophil granulocyte is a key factor in cellular innate defence mechanisms against infection or tissue damage. Granulocyte apoptosis is now acknowledged to have a critical role in progression of inflammatory responses. Granulocytes are preprogrammed to die with important physiological mechanisms for non-inflammatory clearance. Shutdown of secretory capacity represents an important aspect of the programme of biochemical events that accompany neutrophil apoptosis together with surface molecular changes that serve to identify apoptotic cells as targets for phagocytic removal. Defining the underlying regulatory mechanisms together with the changes in patterns of gene/protein expression associated with granulocyte death remains a challenge. Use of novel strategies for inducing cell death will allow biochemical approaches to dissect the underlying pathways. Although study of granulocyte cell death has especial difficulties when compared with other cell types, there are clearly potential benefits for new therapeutic approaches to treat inflammatory diseases.

scholarly journals Tissue Microenvironments within Functional Cortical Subdivisions Adjacent to Focal Stroke

2003 ◽  
Vol 23 (9) ◽  
pp. 997-1009 ◽  
Author(s):  
Diana Katsman ◽  
Jian Zheng ◽  
Kateri Spinelli ◽  
S. Thomas Carmichael
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Heat Shock ◽  
Heat Shock Protein ◽  
Somatosensory Cortex ◽  
Oxidative Dna Damage ◽  
Apoptotic Cell ◽  
Reactive Gliosis ◽  
Ischemic Damage ◽  
Infarct Core

Stroke produces a region of complete cell death and areas of partial damage, injury, and gliosis. The spatial relationship of these regions of damage to the infarct core and within spared neuronal circuits has not been identified. A model of cortical stroke was developed within functional subsets of the somatosensory cortex. Infarct size, regions of apoptosis, oxidative DNA damage, heat shock protein induction, and subtypes of reactive gliosis were precisely mapped with the somatosensory body map, quantified, and interrelated. Three tissue microenvironments were recognized: zones of partial ischemic damage, heat shock protein induction, and distributed gliosis. These three zones involved progressively more distant cortical regions, each larger than the infarct core. The zone of partial ischemic damage represents an overlap region of apoptotic cell death, oxidative DNA damage, loss of synaptic connections, and local reactive gliosis. The zone of distributed gliosis occupies distinct functional areas of the somatosensory cortex. The tissue reorganization induced by stroke is much larger than the stroke site itself. Adjacent tissue microenvironments are sites of distinct reactive cellular signaling and may serve as a link between the processes of acute cell death and delayed neuronal plasticity after focal stroke.

scholarly journals The protein tyrosine kinase SYK regulates the alternative p38 activation in liver during acute liver inflammation

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bo-Ram Bang ◽  
Kyung Ho Han ◽  
Goo-Young Seo ◽  
Michael Croft ◽  
Young Jun Kang
Keyword(s):  
Cell Death ◽  
Liver Injury ◽  
Host Defense ◽  
Protein Tyrosine Kinase ◽  
Inflammatory Responses ◽  
Acute Liver Injury ◽  
Critical Role ◽  
Liver Inflammation ◽  
Hepatocyte Death

AbstractTwo distinct p38 signaling pathways, classical and alternative, have been identified to regulate inflammatory responses in host defense and disease development. The role of alternative p38 activation in liver inflammation is elusive, while classical p38 signaling in hepatocytes plays a role in regulating the induction of cell death in autoimmune-mediated acute liver injury. In this study, we found that a mutation of alternative p38 in mice augmented the severity of acute liver inflammation. Moreover, TNF-induced hepatocyte death was augmented by a mutation of alternative p38, suggesting that alternative p38 signaling in hepatocytes contributed more significantly to the pathology of acute liver injury. Furthermore, SYK-Vav-1 signaling regulates alternative p38 activation and the downregulation of cell death in hepatocytes. Therefore, it is suggested that alternative p38 signaling in the liver plays a critical role in the induction and subsequent pathological changes of acute liver injury. Collectively, our results imply that p38 signaling in hepatocytes plays a crucial role to prevent excessive liver injury by regulating the induction of cell death and inflammation.

Reduction of regional cerebral blood flow during brain retraction pressure in the rat

1982 ◽  
Vol 56 (6) ◽  
pp. 826-829 ◽  
Author(s):  
Jarl Rosenørn ◽  
Nils H. Diemer
Keyword(s):  
Blood Flow ◽  
Cerebral Blood Flow ◽  
Regional Cerebral Blood Flow ◽  
Brain Cortex ◽  
Focal Cerebral Ischemia ◽  
Brain Infarction ◽  
Ischemic Damage ◽  
Regional Cerebral Blood ◽  
Content Type ◽  
Brain Retraction

✓ The use of brain retractors in intracranial operations may lead to focal cerebral ischemia and thereby cause brain infarction. To estimate the risk of ischemic damages, the authors investigated the regional cerebral blood flow (rCBF) in rats by means of autoradiography with 14C-iodoantipyrine at different brain retractor pressures (BRP). A reduction in rCBF to between 10 and 75 ml/100 gm/min with 20 mm Hg of BRP for 30 minutes was found in brain cortex lying under the retractor (normal 55 to 150 ml/100 gm/min). With a BRP of 30 mm Hg for 30 minutes, rCBF was reduced to between 0 and 40 ml/100 gm/min, and with a BRP of 40 mm Hg for 15 minutes rCBF was 0 to 15 ml/100 gm/min. The rCBF in the basal ganglia remained unchanged. Even with a BRP of 20 mm Hg for 30 minutes, there seemed to be a risk of focal ischemic damage.

Hispolon Suppresses LPS- or LTA-Induced iNOS/NO Production and Apoptosis in BV-2 Microglial Cells

2017 ◽  
Vol 45 (08) ◽  
pp. 1649-1666 ◽  
Author(s):  
Ming-Shun Wu ◽  
Chih-Chiang Chien ◽  
Kur-Ta Cheng ◽  
Gottumukkala V. Subbaraju ◽  
Yen-Chou Chen
Keyword(s):  
Cell Death ◽  
Methyl Ester ◽  
Protein Expression ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Microglial Cells ◽  
No Production ◽  
Dna Ladder ◽  
No Donor ◽  
Induced Apoptosis

Hispolon (HIS) is an active polyphenol compound derived from Phellinus linteus (Berkeley & Curtis), and our previous study showed that HIS effectively inhibited inflammatory responses in macrophages [Yang, L.Y., S.C. Shen, K.T. Cheng, G.V. Subbaraju, C.C. Chien and Y.C. Chen. Hispolon inhibition of inflammatory apoptosis through reduction of iNOS/NO production via HO-1 induction in macrophages. J. Ethnopharmacol. 156: 61–72, 2014]; however, its effect on neuronal inflammation is still undefined. In this study, HIS concentration- and time-dependently inhibited lipopolysaccharide (LPS)- and lipoteichoic acid (LTA)-induced inducible nitric oxide (NO) synthase (iNOS)/NO production with increased heme oxygenase (HO)-1 proteins in BV-2 microglial cells. Accordingly, HIS protected BV-2 cells from LPS- or LTA-induced apoptosis, characterized by decreased DNA ladder formation, and caspase-3 and poly(ADP ribose) polymerase (PARP) protein cleavage in BV-2 cells. Similarly, the NOS inhibitor, N-nitro-L-arginine methyl ester (NAME), inhibited LPS- or LTA-induced apoptosis of BV-2 cells, but neither NAME nor HIS showed any inhibition of NO production or cell death induced by the NO donor, sodium nitroprusside (SNP), indicating the involvement of NO in the inflammatory apoptosis of microglial cells. Activation of c-Jun N-terminal kinase (JNK) and nuclear factor (NF)-[Formula: see text]B contributed to LPS- or LTA-induced iNOS/NO production and apoptosis of BV-2 cells, and that was suppressed by HIS. Additionally, HIS possesses activity to induce HO-1 protein expression via activation of extracellular signal-regulated kinase (ERK) in BV-2 cells, and application of the HO inhibitor, tin protoporphyrin (SnPP), or knockdown of HO-1 protein by HO-1 small interfering (si)RNA significantly reversed HIS inhibition of NO production and cell death in BV-2 cells stimulated by LPS. Results of an analysis of the effects of HIS and two structurally related chemicals, i.e. dehydroxy-HIS (D-HIS) and HIS-methyl ester (HIS-ME), showed that HIS expressed the most potent inhibitory effects on iNOS/NO production, JNK activation, and apoptosis in BV-2 microglial cells activated by LPS with increased HO-1 protein expression. Overall these results suggested that HIS possesses inhibitory activity against LPS- or LTA-induced inflammatory responses including iNOS/NO production and apoptosis in BV-2 microglial cells and that the mechanisms involve upregulation of the HO-1 protein and downregulation of JNK/NF-[Formula: see text]B activation. A critical role of hydroxyl at position C3 in the anti-inflammatory actions of HIS against activated BV-2 microglial cells was suggested.

Sign in / Sign up

Export Citation Format

Share Document