MRP8/MRP14 impairs endothelial integrity and induces a caspase-dependent and -independent cell death program

Blood ◽  
2006 ◽  
Vol 109 (6) ◽  
pp. 2453-2460 ◽  
Author(s):  
Dorothee Viemann ◽  
Katarzyna Barczyk ◽  
Thomas Vogl ◽  
Ute Fischer ◽  
Cord Sunderkötter ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Dna Fragmentation ◽  
Calcium Binding ◽  
Inflammatory Diseases ◽  
Membrane Damage ◽  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Endothelial Damage ◽  
Target Cells

Abstract Activated phagocytes express considerable amounts of MRP8 and MRP14, 2 calcium-binding S100 proteins forming stable heterodimers that are specifically secreted at inflammatory sites in many diseases. We previously reported that treatment of human microvascular endothelial cells with purified MRP8/MRP14 leads to loss of endothelial cell contacts. In this study, we demonstrate that MRP8/MRP14 complexes furthermore trigger cell death of endothelial cells after the onset of cell detachment. Morphologic analysis of dying endothelial cells revealed characteristic features of both apoptosis and necrosis. Furthermore, MRP8/MRP14 induced apoptotic caspase-9 and caspase-3 activation, DNA fragmentation, and membrane phosphatidylserine exposure in target cells. These events were independent of death receptor signaling and in part controlled by a mitochondrial pathway. Consistently, overexpression of antiapoptotic Bcl-2 abrogated caspase activation and externalization of phosphatidylserine; however, MRP8/MRP14 still induced plasma membrane damage and even DNA fragmentation. Thus, our results demonstrate that MRP8/MRP14 triggers cell death via caspase-dependent as well as -independent mechanisms. Excessive release of cytotoxic MRP8/MRP14 by activated phagocytes might therefore present an important molecular pathomechanism contributing to endothelial damage during vasculitis and other inflammatory diseases.

scholarly journals Apoptosis and inflammation

1995 ◽  
Vol 4 (1) ◽  
pp. 5-15 ◽  
Author(s):  
C. Haanen ◽  
I. Vermes
Keyword(s):  
Cell Death ◽  
Inflammatory Reaction ◽  
Inflammatory Diseases ◽  
Apoptotic Cell ◽  
Cell Damage ◽  
Target Cells ◽  
Apoptotic Bodies ◽  
Accidental Injury ◽  
Inflammatory Reactions ◽  
Inflammatory Processes

During the last few decades it has been recognized that cell death is not the consequence of accidental injury, but is the expression of a cell suicide programme. Kerr et al. (1972) introduced the term apoptosis. This form of cell death is under the influence of hormones, growth factors and cytokines, which depending upon the receptors present on the target cells, may activate a genetically controlled cell elimination process. During apoptosis the cell membrane remains intact and the cell breaks into apoptotic bodies, which are phagocytosed. Apoptosis, in contrast to necrosis, is not harmful to the host and does not induce any inflammatory reaction. The principal event that leads to inflammatory disease is cell damage, induced by chemical/physical injury, anoxia or starvation. Cell damage means leakage of cell contents into the adjacent tissues, resulting in the capillary transmigration of granulocytes to the injured tissue. The accumulation of neutrophils and release of enzymes and oxygen radicals enhances the inflammatory reaction. Until now there has been little research into the factors controlling the accumulation and the tissue load of granulocytes and their histotoxic products in inflammatory processes. Neutrophil apoptosis may represent an important event in the control of intlamtnation. It has been assumed that granulocytes disintegrate to apoptotic bodies before their fragments are removed by local macrophages. Removal of neutrophils from the inflammatory site without release of granule contents is of paramount importance for cessation of inflammation. In conclusion, apoptotic cell death plays an important role in inflammatory processes and in the resolution of inflammatory reactions. The facts known at present should stimulate further research into the role of neutrophil, eosinophil and macrophage apoptosis in inflammatory diseases.

Arsenic Trioxide-Induced Cell Death Occurs Partially Independent of the Pro-Apoptotic Bcl-2-Family Members Bax and Bak.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4585-4585
Author(s):  
Christian Scholz ◽  
Antje Richter ◽  
Anja Richter ◽  
Bernd Dörken ◽  
Peter T. Daniel
Keyword(s):  
Cell Death ◽  
Arsenic Trioxide ◽  
Cell Lines ◽  
Apoptotic Cell ◽  
Family Members ◽  
Death Receptor ◽  
Hematologic Malignancies ◽  
Mitochondrial Pathway ◽  
Cell Death Pathways

Abstract Arsenic trioxide (As2O3, arsenite) efficiently kills cells from various hematologic malignancies and has successfully been employed for the treatment of acute promyelocytic leukaemia, myelodysplastic syndrome, and multiple myeloma. Investigating the mechanisms of arsenic trioxide-induced cell death, we recently demonstrated that arsenite-mediated cell demise has a partially necrotic phenotype, occurs independently of the extrinsic death receptor pathway of apoptosis, and is not hampered by the absence of functioning caspases. On the contrary, cell death proceeded entirely via an intrinsic, mitochondrial pathway and was efficiently blocked by the anti-apoptotic Bcl-2 family members Bcl-2 or Bcl-xL. Here, we address the role of the pro-apoptotic multi-domain Bcl-2 family members Bax and Bak. By employing different cell lines deficient for Bax and/or Bak, we demonstrate that Bax- or Bak-deficiency as well as the combined absence only partially blocks arsenite-induced cell death. While the detection of an additive effect of the combined Bax-/Bak-deficiency argues for a non redundant function of Bax and Bak, the persistence of a substantial percentage of arsenite-mediated cell demise in different double deficient cell lines nevertheless suggests a mode of arsenic trioxide-mediated cell death independent from these central inducers of apoptotic cell demise. The presented data add to the notion that arsenic trioxide kills tumor cells independent of the apoptotic machinery, and warrants further investigation on the efficacy of this compound in malignancies with deficiencies of the apoptotic cell death pathways.

REDUCED EXPRESSION OF FLICE-INHIBITORY PROTEIN (FLIP) AND NFκB IS ASSOCIATED WITH DEATH RECEPTOR-INDUCED CELL DEATH IN HUMAN AORTIC ENDOTHELIAL CELLS (HAECs)

Cytokine ◽  
2001 ◽  
Vol 15 (2) ◽  
pp. 66-74 ◽  
Author(s):  
Yasunori Okada ◽  
Masahiko Kato ◽  
Hisanori Minakami ◽  
Yoshinari Inoue ◽  
Akihiro Morikawa ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Death Receptor ◽  
Inhibitory Protein ◽  
Aortic Endothelial Cells ◽  
Human Aortic Endothelial Cells ◽  
Aortic Endothelial

scholarly journals FLIP Protects against Hypoxia/Reoxygenation-Induced Endothelial Cell Apoptosis by Inhibiting Bax Activation

2005 ◽  
Vol 25 (11) ◽  
pp. 4742-4751 ◽  
Author(s):  
Xue Wang ◽  
Yong Wang ◽  
Jinglan Zhang ◽  
Hong Pyo Kim ◽  
Stefan W. Ryter ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Plasma Membrane ◽  
Golgi Apparatus ◽  
Death Receptor ◽  
Mouse Lung ◽  
Caspase 8 ◽  
Apoptotic Pathways ◽  
Disc Formation ◽  
Hypoxia Reoxygenation

ABSTRACT Hypoxia/reoxygenation causes cell death, yet the underlying regulatory mechanisms remain partially understood. Recent studies demonstrate that hypoxia/reoxygenation can activate death receptor and mitochondria-dependent apoptotic pathways, involving Bid and Bax mitochondrial translocation and cytochrome c release. Using mouse lung endothelial cells (MLEC), we examined the role of FLIP, an inhibitor of caspase 8, in hypoxia/reoxygenation-induced cell death. FLIP protected MLEC against hypoxia/reoxygenation by blocking both caspase 8/Bid and Bax/mitochondrial apoptotic pathways. FLIP inhibited Bax activation in wild-type and Bid−/− MLEC, indicating independence from the caspase 8/Bid pathway. FLIP also inhibited the expression and activation of protein kinase C (PKC) (α, ζ) during hypoxia/reoxygenation and promoted an association of inactive forms of PKC with Bax. Surprisingly, FLIP expression also inhibited death-inducing signal complex (DISC) formation in the plasma membrane and promoted the accumulation of the DISC in the Golgi apparatus. FLIP expression also upregulated Bcl-XL, an antiapoptotic protein. In conclusion, FLIP decreased DISC formation in the plasma membrane by blocking its translocation from the Golgi apparatus and inhibited Bax activation through a novel PKC-dependent mechanism. The inhibitory effects of FLIP on Bax activation and plasma membrane DISC formation may play significant roles in protecting endothelial cells from the lethal effects of hypoxia/reoxygenation.

Autophagy, immunological response, and inflammation all rely on the TRIM family proteins. TRIM-based therapeutics for inflammatory illnesses including diabetes and diabetic comorbidities are promising

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Cell Death ◽  
Diabetic Complications ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Neurological Diseases ◽  
Membrane Damage ◽  
Cell Mass ◽  
Immunological Response ◽  
Insulin Synthesis ◽  
Trim Proteins

Autophagy is a system that recycles for cellular repair and stability. TRIM regulates the autophagy and pyroptotic pathways. Autophagy, immunological response, and inflammation all rely on the TRIM family proteins. Changes in TRIM function or expression are prevalent in people with diabetes. Yoshinori Ohsumi discovered ATG in yeast genetic screening. Many yeast autophagy pathways are shared across yeast and humans. The TRIMFamily impacts autophagosome and Pyroptosis, controlling both of these processes. This will examine the TrIM family's function in diabetes and diabetic complications. The treatment of acute myeloid leukemia (AML) with chemotherapy reduces the chance of malignancy. The way TRIM proteins regulate autophagy is unclear. TRIM proteins have been found to participate in pyroptotic cell death via inflammasomes. This study might lead to greater understanding of TRIM-based therapeutics for inflammatory illnesses including diabetes and diabetic comorbidities. NLRP3 is triggered by both infection-related plasma membrane damage and ROS-induced activation of the inflammasome. Human caspases 1 and 4/5 and mouse caspase 11 are activated by inflammasomes. Caspases cleave GSDMD, the most well-studied member of the gasdermin family.Pyroptosis and the generation of inflammatory cytokines are both catalyzed by Gasdermin D. Circular perforations in membranes release mature cytokines and cell lysis. Each step of Pyroptotic cell death is influenced by several circumstances. Several TRIM proteins have been shown to mediate pyroptotic cell death via inflammasomes. TRIM30, for example, inhibits NLRP3-mediated inflammation by regulating ROS levels. NLRP1 and NLRP2 require NFB to activate and assemble. TRIM family proteins (such as TRIM59, TRIM9, and TRIM39) have been associated with inflammation in various studies. Additional study on TRIM protein's impact on pyroposis is required. Inflammatory responses triggered by inflammasomes are commonly connected to diabetes, gout, and neurological diseases, including Alzheimer's disease. Functional cell mass loss is a key pathophysiology of DM. The role of TRIM proteins in pyroptotic cell death will provide new insights for TRIM-based therapies for specific inflammatory diseases in the clinic.Auto-Phagy and Pyraptosis mediate IL1 activation in T1DM and T2DM. Hyperglycemia boosts NLRP3-induced inflammation, which yields IL1 Higher levels of IL-1 in the islet microenvironment increase pro-apoptotic signaling. Activation of the innate immune system reduces insulin synthesis, which is the foundation of diabetes. Diabetes and diabetic complications are correlated with the TRIM family proteins. Liver and skeletal muscle tissues are shown to have TRIM32-dependent insulin resistance. Recent studies concluded that TRIM72 was not a cause of DM. We need more research to determine the importance of TRim72 in diabetes, and perhaps a novel therapeutic target may be discovered.

scholarly journals Hepatocyte Death: A Clear and Present Danger

2010 ◽  
Vol 90 (3) ◽  
pp. 1165-1194 ◽  
Author(s):  
Harmeet Malhi ◽  
Maria Eugenia Guicciardi ◽  
Gregory J. Gores
Keyword(s):  
Cell Death ◽  
Fatty Acid ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Enterohepatic Circulation ◽  
Tissue Injury ◽  
Death Receptor ◽  
Mitochondrial Pathway ◽  
Hepatocyte Injury ◽  
The Unfolded Protein Response

The hepatocyte is especially vulnerable to injury due to its central role in xenobiotic metabolism including drugs and alcohol, participation in lipid and fatty acid metabolism, its unique role in the enterohepatic circulation of bile acids, the widespread prevalence of hepatotropic viruses, and its existence within a milieu of innate immune responding cells. Apoptosis and necrosis are the most widely recognized forms of hepatocyte cell death. The hepatocyte displays many unique features regarding cell death by apoptosis. It is quite susceptible to death receptor-mediated injury, and its death receptor signaling pathways involve the mitochondrial pathway for efficient cell killing. Also, death receptors can trigger lysosomal disruption in hepatocytes which further promote cell and tissue injury. Interestingly, hepatocytes are protected from cell death by only two anti-apoptotic proteins, Bcl-xL and Mcl-1, which have nonredundant functions. Endoplasmic reticulum stress or the unfolded protein response contributes to hepatocyte cell death during alterations of lipid and fatty acid metabolism. Finally, the current information implicating RIP kinases in necrosis provides an approach to more fully address this mode of cell death in hepatocyte injury. All of these processes contributing to hepatocyte injury are discussed in the context of potential therapeutic strategies.

Acellular hemoglobin-mediated oxidative stress toward endothelium: a role for ferryl iron

1998 ◽  
Vol 275 (3) ◽  
pp. H1046-H1053 ◽  
Author(s):  
Daniel W. Goldman ◽  
Richard J. Breyer ◽  
David Yeh ◽  
Beth A. Brockner-Ryan ◽  
Abdu I. Alayash
Keyword(s):  
Hydrogen Peroxide ◽  
Endothelial Cells ◽  
Cell Death ◽  
Dna Fragmentation ◽  
Apoptotic Cell ◽  
Morphological Changes ◽  
Blood Substitutes ◽  
Apoptotic Cell Death ◽  
Redox Activity ◽  
Chemically Modified

We tested the hypothesis that chemical modifications used to produce stable, oxygen-carrying, Hb-based blood substitutes can induce cytotoxicity in endothelial cells in culture because of altered redox activity. We examined the interaction of hydrogen peroxide with nonmodified hemoglobin (HbA0) and two chemically modified hemoglobins, α-cross-linked hemoglobin (α-DBBF) and its polymerized form (poly-α-DBBF). Hydrogen peroxide-induced cell death (as assessed by lactate dehydrogenase release) in bovine aortic endothelial cells (BAEC) was completely inhibited by all three hemoglobin preparations, consistent with their known pseudoperoxidase activity [hemoglobin consumes peroxide as it cycles between ferric (Fe3+) and ferryl (Fe4+) hemes]. However, reaction of the modified hemoglobins, but not HbA0, with hydrogen peroxide induced apoptotic cell death (as assessed by morphological changes and DNA fragmentation) that correlated with the formation of a long-lived ferrylhemoglobin. A preparation of ferryl-α-DBBF free of residual peroxide rapidly induced morphological changes and DNA fragmentation in BAEC, indicative of apoptotic cell death. Redox cycling of chemically modified hemoglobins by peroxide yielded a persistent ferryl iron that was cytotoxic to endothelial cells.

Macrophages induce apoptosis in normal cells in vivo

Development ◽  
1997 ◽  
Vol 124 (18) ◽  
pp. 3633-3638 ◽  
Author(s):  
G. Diez-Roux ◽  
R.A. Lang
Keyword(s):  
Endothelial Cells ◽  
Cell Death ◽  
Programmed Cell Death ◽  
Direct Evidence ◽  
Vascular Endothelial Cells ◽  
Target Cells ◽  
Vascular Endothelial ◽  
Normal Cells ◽  
Apoptotic Morphology

It is well established that macrophages have a function in scavenging apoptotic bodies from cells undergoing programmed cell death. Here we show that macrophages can also induce apoptosis of normal cells. Using injected toxic liposomes to eliminate macrophages in the anterior chamber of the rat eye, we provide direct evidence that, in vivo, macrophages induce apoptosis in normal vascular endothelial cells during programmed capillary regression. Macrophage elimination resulted in the survival of endothelial cells that normally would die and the persistence of functional capillaries. Furthermore, replacement of eliminated macrophages with bone-marrow-derived macrophages ‘rescued’ lack of capillary regression. Viability of the persistent target cells was demonstrated through their lack of apoptotic morphology, expression of intracellular esterases and synthesis of DNA. These results uncover a new function for macrophages in the remodeling of tissues through the induction of programmed cell death and provide direct evidence of a key role for macrophages in capillary regression.

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