Human NLRP1: From the shadows to center stage

In response to infection or cell damage, inflammasomes form intracellular multimeric protein complexes that play an essential role in host defense. Activation results in the maturation and subsequent secretion of pro-inflammatory cytokines of the IL-1 family and a specific cell death coined pyroptosis. Human NLRP1 was the first inflammasome-forming sensor identified at the beginning of the millennium. However, its functional relevance and its mechanism of activation have remained obscure for many years. Recent discoveries in the NLRP1 field have propelled our understanding of the functional relevance and molecular mode of action of this unique inflammasome sensor, which we will discuss in this perspective.

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Neutrophil Extracellular Traps: A Potential Therapeutic Target in MPO-ANCA Associated Vasculitis?

Frontiers in Immunology ◽

10.3389/fimmu.2021.635188 ◽

2021 ◽

Vol 12 ◽

Author(s):

Kim M. O'Sullivan ◽

Stephen R. Holdsworth

Keyword(s):

Cell Death ◽

Autoimmune Disease ◽

Host Defense ◽

Cell Damage ◽

Severe Disease ◽

Therapeutic Targets ◽

Target Surface ◽

Immune Recognition ◽

Critical Pathways ◽

Recognition And Response

Our understanding of immune recognition and response to infection and non-infectious forms of cell damage and death is rapidly increasing. The major focus is on host immunity and microbiological invasion. However, it is also clear that these same pathways are important in the initiation and maintenance of autoimmunity and the damage caused to targeted organs. Understanding the involvement of cell death in autoimmune disease is likely to help define critical pathways in the immunopathogenesis of autoimmune disease and new therapeutic targets. An important immune responder cell population in host defense and autoimmunity is the neutrophil. One autoimmune disease where neutrophils play important roles is MPO-ANCA Microscopic Vasculitis. This a severe disease that results from inflammation to small blood vessels in the kidney, the glomeruli (high blood flow and pressure filters). One of the best studied ways in which neutrophils participate in this disease is by cell death through NETosis resulting in the discharge of proinflammatory enzymes and nuclear fragments. In host defense against infection this process helps neutralize pathogens however in auto immunity NETosis results in injury and death to the surrounding healthy tissues. The major autoimmune target in this disease is myeloperoxidase (MPO) which is found uniquely in the cytoplasm of neutrophils. Although the kidney is the major organ targeted in this disease MPO is not expressed in the kidney. Autoantibodies target surface MPO on activated circulating neutrophils resulting in their lodgment in glomerular capillaries where they NETose releasing extracellularly MPO and nuclear fragments initiating injury and planting the key autoantigen MPO. It is the cell death of neutrophils that changes the kidney from innocent bystander to major autoimmune target. Defining the immunopathogenesis of this autoimmune disease and recognizing critical injurious pathways will allow therapeutic intervention to block these pathways and attenuate autoimmune injury. The insights (regarding mechanisms of injury and potential therapeutic targets) are likely to be highly relevant to many other autoimmune diseases.

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Alpha-Tocopherol Protects Cultured Human Cells from the Acute Lethal Cytotoxicity of Dioxin

International Journal for Vitamin and Nutrition Research ◽

10.1024/0300-9831.72.3.147 ◽

2002 ◽

Vol 72 (3) ◽

pp. 147-153 ◽

Cited By ~ 8

Author(s):

Kei-Ichi Hirai ◽

Jie-Hong Pan ◽

Ying-Bo Shui ◽

Eriko Simamura ◽

Hiroki Shimada ◽

...

Keyword(s):

Cell Death ◽

Cell Damage ◽

Smooth Endoplasmic Reticulum ◽

Dehydroascorbic Acid ◽

Human Cells ◽

Alpha Tocopherol ◽

Cervical Cancer Cells ◽

Cultured Human Cells ◽

Nuclear Damage ◽

Conjunctival Epithelial Cells

The possible protection of cultured human cells from acute dioxin injury by antioxidants was investigated. The most potent dioxin, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), caused vacuolization of the smooth endoplasmic reticulum and Golgi apparatus in cultured human conjunctival epithelial cells and cervical cancer cells. Subsequent nuclear damage included a deep irregular indentation resulting in cell death. A dosage of 30–40 ng/mL TCDD induced maximal intracellular production of H2O2 at 30 minutes and led to severe cell death (0–31% survival) at two hours. A dose of 1.7 mM alpha-tocopherol or 1 mM L-dehydroascorbic acid significantly protected human cells against acute TCDD injuries (78–97% survivals), but vitamin C did not provide this protection. These results indicate that accidental exposure to fatal doses of TCDD causes cytoplasmic free radical production within the smooth endoplasmic reticular systems, resulting in severe cytotoxicity, and that vitamin E and dehydroascorbic acid can protect against TCDD-induced cell damage.

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Phagoptosis - Cell Death By Phagocytosis - Plays Central Roles in Physiology, Host Defense and Pathology

Current Molecular Medicine ◽

10.2174/156652401509151105130628 ◽

2015 ◽

Vol 15 (9) ◽

pp. 842-851 ◽

Cited By ~ 26

Author(s):

G. Brown ◽

A. Vilalta ◽

M. Fricker

Keyword(s):

Cell Death ◽

Host Defense

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Inhibition of Autophagy Potentiated Hippocampal Cell Death Induced by Endoplasmic Reticulum Stress and its Activation by Trehalose Failed to be Neuroprotective

Current Neurovascular Research ◽

10.2174/1567202616666190131155834 ◽

2019 ◽

Vol 16 (1) ◽

pp. 3-11

Author(s):

Luisa Halbe ◽

Abdelhaq Rami

Keyword(s):

Endoplasmic Reticulum ◽

Cell Death ◽

Er Stress ◽

Cell Damage ◽

Protective Mechanism ◽

Unfolded Proteins ◽

Neuronal Viability ◽

Hippocampal Cell ◽

Trigger Cell Death ◽

Autophagy Inhibition

Introduction: Endoplasmic reticulum (ER) stress induced the mobilization of two protein breakdown routes, the proteasomal- and autophagy-associated degradation. During ERassociated degradation, unfolded ER proteins are translocated to the cytosol where they are cleaved by the proteasome. When the accumulation of misfolded or unfolded proteins excels the ER capacity, autophagy can be activated in order to undertake the degradative machinery and to attenuate the ER stress. Autophagy is a mechanism by which macromolecules and defective organelles are included in autophagosomes and delivered to lysosomes for degradation and recycling of bioenergetics substrate. Materials and Methods: Autophagy upon ER stress serves initially as a protective mechanism, however when the stress is more pronounced the autophagic response will trigger cell death. Because autophagy could function as a double edged sword in cell viability, we examined the effects autophagy modulation on ER stress-induced cell death in HT22 murine hippocampal neuronal cells. We investigated the effects of both autophagy-inhibition by 3-methyladenine (3-MA) and autophagy-activation by trehalose on ER-stress induced damage in hippocampal HT22 neurons. We evaluated the expression of ER stress- and autophagy-sensors as well as the neuronal viability. Results and Conclusion: Based on our findings, we conclude that under ER-stress conditions, inhibition of autophagy exacerbates cell damage and induction of autophagy by trehalose failed to be neuroprotective.

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The STING1 network regulates autophagy and cell death

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-021-00613-4 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Ruoxi Zhang ◽

Rui Kang ◽

Daolin Tang

Keyword(s):

Cell Death ◽

Mitotic Cell ◽

Therapeutic Interventions ◽

Type I Interferons ◽

Microbial Pathogens ◽

Type I ◽

Autophagic Degradation ◽

Health And Disease ◽

Shed Light ◽

Pro Inflammatory Cytokines

AbstractCell death and immune response are at the core of life. In past decades, the endoplasmic reticulum (ER) protein STING1 (also known as STING or TMEM173) was found to play a fundamental role in the production of type I interferons (IFNs) and pro-inflammatory cytokines in response to DNA derived from invading microbial pathogens or damaged hosts by activating multiple transcription factors. In addition to this well-known function in infection, inflammation, and immunity, emerging evidence suggests that the STING1-dependent signaling network is implicated in health and disease by regulating autophagic degradation or various cell death modalities (e.g., apoptosis, necroptosis, pyroptosis, ferroptosis, mitotic cell death, and immunogenic cell death [ICD]). Here, we outline the latest advances in our understanding of the regulating mechanisms and signaling pathways of STING1 in autophagy and cell death, which may shed light on new targets for therapeutic interventions.

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Apoptosis and inflammation

Mediators of Inflammation ◽

10.1155/s0962935195000020 ◽

1995 ◽

Vol 4 (1) ◽

pp. 5-15 ◽

Cited By ~ 68

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.

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Pancreatic islet cell survival following islet isolation: the role of cellular interactions in the pancreas

Journal of Endocrinology ◽

10.1677/joe.0.1610357 ◽

1999 ◽

Vol 161 (3) ◽

pp. 357-364 ◽

Cited By ~ 102

Author(s):

A Ilieva ◽

S Yuan ◽

RN Wang ◽

D Agapitos ◽

DJ Hill ◽

...

Keyword(s):

Cell Death ◽

Cell Survival ◽

Islet Cell ◽

Apoptotic Cell ◽

Specific Cell ◽

Cellular Interactions ◽

Pancreatic Islet Cell ◽

Beneficial Result ◽

Trophic Effect ◽

Ductal Epithelium

The purpose of this study was to characterize the trophic effect of pancreatic duct cells on the islets of Langerhans. Ductal epithelium and islets were isolated from hamster pancreata. In addition, duct-conditioned medium (DCM) was prepared from primary duct cultures that had been passaged twice to remove other cellular elements. Three experimental groups were then established: Group 1, 100 islets alone; Group 2, 100 islets+80 duct fragments; and Group 3, 100 islets in 25% DCM. All tissues were embedded in rat tail collagen for up to 12 days and the influence of pancreatic ductal epithelium on islet cell survival was examined. By day 12, 20.6+/-3. 0% (S.E.M.) of the islets cultured alone developed central necrosis, compared with 6.7+/-2.0% of the islets co-cultured with ducts and 5.6+/-1.5% of the islets cultured in DCM (P<0.05). The presence of apoptotic cell death was determined by a TdT-mediated dUTP-biotin nick end labelling (TUNEL) assay and by a specific cell death ELISA. DNA fragmentation in islets cultured alone was significantly increased compared with islets cultured either in the presence of duct epithelium or in DCM (P<0.05). More than 80% of TUNEL-positive cells were situated in the inner 80% of the islet area, suggesting that most were beta-cells. DCM was analysed for known growth factors. The presence of a large amount of IGF-II (34 ng/ml) and a much smaller quantity of nerve growth factor (4 ng/ml) was identified. When the apoptosis studies were repeated to compare islets alone, islets+DCM and islets+IGF-II, the cell death ELISA indicated that IGF-II produced the same beneficial result as DCM when compared with islets cultured alone. We conclude that pancreatic ductal epithelium promotes islet cell survival. This effect appears to be mediated in a paracrine manner by the release of IGF-II from cells in the ductal epithelium.

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Inflammasomes inMycobacterium tuberculosis-Driven Immunity

Canadian Journal of Infectious Diseases and Medical Microbiology ◽

10.1155/2017/2309478 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 8

Author(s):

Sebastian Wawrocki ◽

Magdalena Druszczynska

Keyword(s):

Mycobacterium Tuberculosis ◽

Inflammatory Response ◽

Immune Responses ◽

Proinflammatory Cytokines ◽

Immune Cells ◽

Protein Complexes ◽

Inflammasome Activation ◽

Host Immune Responses ◽

Multimeric Protein

The development of effective innate and subsequent adaptive host immune responses is highly dependent on the production of proinflammatory cytokines that increase the activity of immune cells. The key role in this process is played by inflammasomes, multimeric protein complexes serving as a platform for caspase-1, an enzyme responsible for proteolytic cleavage of IL-1βand IL-18 precursors. Inflammasome activation, which triggers the multifaceted activity of these two proinflammatory cytokines, is a prerequisite for developing an efficient inflammatory response against pathogenicMycobacterium tuberculosis(M.tb). This review focuses on the role of NLRP3 and AIM2 inflammasomes inM.tb-driven immunity.

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Autophagy impairment as a key feature for acetaminophen-induced ototoxicity

Cell Death and Disease ◽

10.1038/s41419-020-03328-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Tong Zhao ◽

Tihua Zheng ◽

Huining Yu ◽

Bo Hua Hu ◽

Bing Hu ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Death ◽

Lysosomal Enzymes ◽

Apoptotic Cell ◽

Cell Damage ◽

Treatment Strategies ◽

Explant Culture ◽

Apoptotic Cell Death ◽

Lysosomal Dysfunction ◽

Autophagic Degradation

AbstractMacroautophagy/autophagy is a highly conserved self-digestion pathway that plays an important role in cytoprotection under stress conditions. Autophagy is involved in hepatotoxicity induced by acetaminophen (APAP) in experimental animals and in humans. APAP also causes ototoxicity. However, the role of autophagy in APAP-induced auditory hair cell damage is unclear. In the present study, we investigated autophagy mechanisms during APAP-induced cell death in a mouse auditory cell line (HEI-OC1) and mouse cochlear explant culture. We found that the expression of LC3-II protein and autophagic structures was increased in APAP-treated HEI-OC1 cells; however, the degradation of SQSTM1/p62 protein, the yellow puncta of mRFP-GFP-LC3 fluorescence, and the activity of lysosomal enzymes decreased in APAP-treated HEI-OC1 cells. The degradation of p62 protein and the expression of lysosomal enzymes also decreased in APAP-treated mouse cochlear explants. These data indicate that APAP treatment compromises autophagic degradation and causes lysosomal dysfunction. We suggest that lysosomal dysfunction may be directly responsible for APAP-induced autophagy impairment. Treatment with antioxidant N-acetylcysteine (NAC) partially alleviated APAP-induced autophagy impairment and apoptotic cell death, suggesting the involvement of oxidative stress in APAP-induced autophagy impairment. Inhibition of autophagy by knocking down of Atg5 and Atg7 aggravated APAP-induced ER and oxidative stress and increased apoptotic cell death. This study provides a better understanding of the mechanism responsible for APAP ototoxicity, which is important for future exploration of treatment strategies for the prevention of hearing loss caused by ototoxic medications.

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