Statins as anti-pyroptotic agents

IntroductionPyroptosis is a regulated form of cell death, which is often a consequence of the activation of inflammatory caspases.Material and methodsAppropriate inflammatory responses and the induction of pyroptosis enhance the clearance of pathogens and increase innate immunity.ResultsHowever, excessive pyroptosis contributes to a hyperinflammatory response and aggravates tissue damage, thereby causing inflammatory diseases. There have been recent reports on the modulation of pyroptosis by statins, which may explain part of the pleiotropic actions of these drugs in inflammatory diseases and cancer.ConclusionsHerein, the extant evidence for the potential value of statins in targeting pyroptosis in various diseases is reviewed.

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Amphiregulin Regulates Phagocytosis-Induced Cell Death in Monocytes via EGFR and the Bcl-2 Protein Family

Mediators of Inflammation ◽

10.1155/2019/1603131 ◽

2019 ◽

Vol 2019 ◽

pp. 1-13 ◽

Cited By ~ 1

Author(s):

Christopher Platen ◽

Stephan Dreschers ◽

Jessica Wappler ◽

Andreas Ludwig ◽

Stefan Düsterhöft ◽

...

Keyword(s):

Cell Death ◽

Bacterial Infections ◽

Caspase 3 ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Dependent Manner ◽

Intrinsic Apoptosis ◽

Caspase 9 ◽

Apoptosis Pathway ◽

Intrinsic Apoptosis Pathway

Neonates are extremely susceptible to bacterial infections, and evidences suggest that phagocytosis-induced cell death (PICD) is less frequently triggered in neonatal monocytes than in monocytes from adult donors. An insufficient termination of the inflammatory response, leading to a prolonged survival of neonatal monocytes with ongoing proinflammatory cytokine release, could be associated with the progression of various inflammatory diseases in neonates. Our previous data indicate that amphiregulin (AREG) is increasingly expressed on the cell surface of neonatal monocytes, resulting in remarkably higher soluble AREG levels after proteolytic shedding. In this study, we found that E. coli-infected neonatal monocytes show an increased phosphorylation of ERK, increased expression of Bcl-2 and Bcl-XL, and reduced levels of cleaved caspase-3 and caspase-9 compared to adult monocytes. In both cell types, additional stimulation with soluble AREG further increased ERK activation and expression of Bcl-2 and Bcl-XL and reduced levels of cleaved caspase-3 and caspase-9 in an EGFR-dependent manner. These data suggest that reduced PICD of neonatal monocytes could be due to reduced intrinsic apoptosis and that AREG can promote protection against PICD. This reduction of the intrinsic apoptosis pathway in neonatal monocytes could be relevant for severely prolonged inflammatory responses of neonates.

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GITR-GITRL System, A Novel Player in Shock and Inflammation

The Scientific World JOURNAL ◽

10.1100/tsw.2007.106 ◽

2007 ◽

Vol 7 ◽

pp. 533-566 ◽

Cited By ~ 45

Author(s):

Ludovic Tibor Krausz ◽

Rodolfo Bianchini ◽

Simona Ronchetti ◽

Katia Fettucciari ◽

Giuseppe Nocentini ◽

...

Keyword(s):

Innate Immunity ◽

T Cells ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Tumor Necrosis Factor Receptor ◽

Early Response ◽

System A ◽

Antigen Presenting

Glucocorticoid-induced TNFR-Related (GITR) protein is a member of the tumor necrosis factor receptor superfamily that modulates acquired and natural immune response. It is expressed in several cells and tissues, including T cells, natural killer cells, and, at lower levels, in cells of innate immunity. GITR is activated by its ligand, GITRL, mainly expressed on antigen presenting and endothelial cells. Recent evidence suggests that the GITR/GITRL system participates in the development of inflammatory responses, including shock, either due to early response of neutrophils and macrophages, or together with autoimmune/allergic pathogenesis. The pro-inflammatory role of the GITR/GITRL system is due to: 1) modulation of the extravasation process, 2) activation of innate immunity cells, 3) activation of effector T cells also favored by partial inhibition of suppressor T cells and modulation of dendritic function. This review summarizes thein vivorole of the GITR/GITRL system in inflammation and shock, explaining the mechanisms responsible for their effects, considering the interplay among the different cells of the immune system and transduction pathways activated by GITR and GITRL triggering. The hidden aspects about GITR/GITRL function, crucial for treatment planning of inflammatory diseases and shock by modulation of this system is stressed.

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Membrane permeabilization is mediated by distinct epitopes in mouse and human orthologs of the necroptosis effector, MLKL

10.1101/2021.05.03.442385 ◽

2021 ◽

Author(s):

Ashish Sethi ◽

Christopher R Horne ◽

Cheree Fitzgibbon ◽

Karyn L Wilde ◽

Katherine A Davies ◽

...

Keyword(s):

Innate Immunity ◽

Cell Death ◽

Inflammatory Diseases ◽

Upstream Regulator ◽

Cell Death Pathway ◽

Lytic Function ◽

Human Orthologs ◽

Binding Epitope ◽

Kinase Phosphorylation ◽

Terminal Effector

Necroptosis is a lytic programmed cell death pathway with origins in innate immunity that is frequently dysregulated in inflammatory diseases. The terminal effector of the pathway, MLKL, is licensed to kill following phosphorylation of its pseudokinase domain by the upstream regulator, RIPK3 kinase. Phosphorylation provokes the unleashing of MLKL's N-terminal four-helix bundle (4HB or HeLo) domain, which binds and permeabilizes the plasma membrane to cause cell death. The precise mechanism by which the 4HB domain permeabilizes membranes, and how the mechanism differs between species, remains unclear. Here, we identify the membrane binding epitope of mouse MLKL using NMR spectroscopy. Using liposome permeabilization and cell death assays, we validate K69 in the α3 helix, W108 in the α4 helix, and R137/Q138 in the first brace helix as crucial residues for necroptotic signaling. This epitope differs from the phospholipid binding site reported for human MLKL, which comprises basic residues primarily located in the α1 and α2 helices. In further contrast to human and plant MLKL orthologs, in which the α3-α4 loop forms a helix, this loop is unstructured in mouse MLKL in solution. Together, these findings illustrate the versatility of the 4HB domain fold, whose lytic function can be mediated by distinct epitopes in different orthologs.

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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

10.31219/osf.io/y4g6e ◽

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.

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Review: Mammalian peptidoglycan recognition proteins (PGRPs) in innate immunity

Innate Immunity ◽

10.1177/1753425910366059 ◽

2010 ◽

Vol 16 (3) ◽

pp. 168-174 ◽

Cited By ~ 95

Author(s):

Roman Dziarski ◽

Dipika Gupta

Keyword(s):

Innate Immunity ◽

Polymorphonuclear Leukocytes ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Antibacterial Activities ◽

Gram Negative Bacteria ◽

Mucous Membranes ◽

And Function ◽

Bacterial Peptidoglycan ◽

Arthritic Joints

Peptidoglycan recognition proteins (PGRPs or PGLYRPs) are innate immunity proteins that are conserved from insects to mammals, recognize bacterial peptidoglycan, and function in antibacterial immunity and inflammation. Mammals have four PGRPs — PGLYRP1, PGLYRP2, PGLYRP3, and PGLYRP4. They are secreted proteins expressed in polymorphonuclear leukocytes (PGLYRP1), liver (PGLYRP2), or on body surfaces, mucous membranes, and in secretions (saliva, sweat) (PGLYRP3 and PGLYRP4). All PGRPs recognize bacterial peptidoglycan. Three PGRPs, PGLYRP1, PGLYRP3, and PGLYRP4 are directly bactericidal for both Gram-positive and Gram-negative bacteria and have no enzymatic activity, whereas PGLYRP2 is an N-acetylmuramoyl-L-alanine amidase that hydrolyzes bacterial cell wall peptidoglycan. Peptidoglycan recognition proteins influence host— pathogen interactions not only through their antibacterial or peptidoglycan-hydrolytic properties, but also through their pro-inflammatory and anti-inflammatory properties that are independent of their hydrolytic and antibacterial activities. The PGRPs likely play a role both in antibacterial defenses and several inflammatory diseases. They modulate local inflammatory responses in tissues (such as arthritic joints) and there is evidence for association of PGRPs with inflammatory diseases, such as psoriasis.

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

Biochemical Society Transactions ◽

10.1042/bst0320447 ◽

2004 ◽

Vol 32 (3) ◽

pp. 447-451 ◽

Cited By ~ 7

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.

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E3 ubiquitin ligase SYVN1 is a key positive regulator for GSDMD-mediated pyroptosis

10.1101/2021.07.21.453219 ◽

2021 ◽

Author(s):

Yuhua Shi ◽

Yang Yang ◽

Weilv Xu ◽

Wei Xu ◽

Xinyu Fu ◽

...

Keyword(s):

Cell Death ◽

Ubiquitin Ligase ◽

Essential Role ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

E3 Ubiquitin Ligase ◽

Positive Regulator ◽

Ldh Release

Gasdermin D (GSDMD) participates in activation of inﬂammasomes and pyroptosis. Meanwhile, ubiquitination strictly regulates inﬂammatory responses. However, how ubiquitination regulates Gasdermin D activity is not well understood. In this study, we show that pyroptosis triggered by Gasdermin D is regulated through ubiquitination. Specifically, SYVN1, an E3 ubiquitin ligase of gasdermin D, promotes GSDMD-mediated pyroptosis. SYVN1 deﬁciency inhibits pyroptosis and subsequent LDH release and PI uptake. SYVN1 directly interacts with GSDMD, and mediates K27-linked polyubiquitination of GSDMD on K203 and K204 residues, promoting GSDMD-induced pyroptotic cell death. Thus, our findings revealed the essential role of SYVN1 in GSDMD-mediated pyroptosis. Overall, GSDMD ubiquitination is a potential therapeutic module for inflammatory diseases.

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Abstract 13405: Genetic Deletion of Stimulator of Interferon Genes Attenuates Atherogenesis in Apolipoprotein E-deficient Mice

Circulation ◽

10.1161/circ.142.suppl_3.13405 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Phuong T Pham ◽

Daiju Fukuda ◽

Masataka Sata

Keyword(s):

Innate Immunity ◽

Apolipoprotein E ◽

Aortic Arch ◽

Inflammatory Responses ◽

Inflammatory Diseases ◽

Vascular Inflammation ◽

Atherosclerotic Plaques ◽

Atherosclerotic Lesions ◽

Gene And Protein Expression ◽

Inflammatory Molecules

Introduction: Recent studies show the contribution of innate immunity system to the pathogenesis of inflammatory diseases, including atherosclerosis. Stimulation of interferon genes (STING), originally known as a cytosolic DNA sensor, recognizes cytosolic DNA fragments, activating innate immunity. Here, we investigated whether STING contributes to the development of vascular inflammation and atherogenesis in apolipoprotein E-deficient (Apoe –/– ) mice. Methods and Results: The expression of STING increased in the atherosclerotic aorta in both gene and protein expression levels. STING-deficient Apoe –/– (STING –/– Apoe –/– ) mice reduced atherosclerotic lesions in the aortic arch ( P <0.05), along with the reduction of lipid and macrophage accumulation in atherosclerotic plaques ( P <0.05, respectively), and inflammatory molecule expression in the aorta compared with those in Apoe –/– mice after 20 weeks on a western-type diet. Also, pharmacologic blockade of STING in Apoe –/– mice for 12 weeks treatment attenuated atherogenesis in the aortic arch ( P <0.05), reduced the accumulation of lipid in atherosclerotic plaques ( P <0.05) with no alteration of metabolic parameters. Restoration of STING in bone marrow in STING –/– Apoe –/– mice promoted atherogenesis ( P <0.05), lipid deposition ( P <0.05), and vascular inflammation. cGAMP, a specific STING agonist, or mitochondrial DNA extracted from macrophages promoted expression of inflammatory molecules more effectively in Apoe -/- macrophages than in STING –/– Apoe –/– macrophages, while C-176, a specific STING inhibitor, attenuated these inflammatory responses. The results of western blotting showed the involvement of NF-κB and IRF-3 signaling in STING-associated vascular inflammation and macrophage activation. Furthermore, in humans, STING expression was confirmed in atherosclerotic lesions in the carotid artery. Conclusion: STING signaling activates macrophages, promotes vascular inflammation and atherosclerosis in Apoe -/- mice. Our results suggest that STING may serve as a potential therapeutic target for atherosclerosis.

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Oral Dysbiosis and Autoimmunity: From Local Periodontal Responses to an Imbalanced Systemic Immunity. A Review

Frontiers in Immunology ◽

10.3389/fimmu.2020.591255 ◽

2020 ◽

Vol 11 ◽

Author(s):

Lina J. Suárez ◽

Hernan Garzón ◽

Silie Arboleda ◽

Adriana Rodríguez

Keyword(s):

Tissue Damage ◽

Inflammatory Responses ◽

Molecular Mimicry ◽

Inflammatory Diseases ◽

Explanatory Models ◽

Point Of View ◽

Epitope Spreading ◽

Damage Process ◽

Genetic And Environmental Factors ◽

Current Paradigm

The current paradigm of onset and progression of periodontitis includes oral dysbiosis directed by inflammophilic bacteria, leading to altered resolution of inflammation and lack of regulation of the inflammatory responses. In the construction of explanatory models of the etiopathogenesis of periodontal disease, autoimmune mechanisms were among the first to be explored and historically, for more than five decades, they have been described in an isolated manner as part of the tissue damage process observed in periodontitis, however direct participation of these mechanisms in the tissue damage is still controversial. Autoimmunity is affected by genetic and environmental factors, leading to an imbalance between the effector and regulatory responses, mostly associated with failed resolution mechanisms. However, dysbiosis/infection and chronic inflammation could trigger autoimmunity by several mechanisms including bystander activation, dysregulation of toll-like receptors, amplification of autoimmunity by cytokines, epitope spreading, autoantigens complementarity, autoantigens overproduction, microbial translocation, molecular mimicry, superantigens, and activation or inhibition of receptors related to autoimmunity by microorganisms. Even though autoreactivity in periodontitis is biologically plausible, the associated mechanisms could be related to non-pathologic responses which could even explain non-recognized physiological functions. In this review we shall discuss from a descriptive point of view, the autoimmune mechanisms related to periodontitis physio-pathogenesis and the participation of oral dysbiosis on local periodontal autoimmune responses as well as on different systemic inflammatory diseases.

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Resolution of Inflammation in Acute Graft-Versus-Host-Disease: Advances and Perspectives

Biomolecules ◽

10.3390/biom12010075 ◽

2022 ◽

Vol 12 (1) ◽

pp. 75

Author(s):

Layara Roberta Ferreira Duarte ◽

Vanessa Pinho ◽

Barbara Maximino Rezende ◽

Mauro Martins Teixeira

Keyword(s):

Graft Versus Host Disease ◽

Tissue Damage ◽

Inflammatory Responses ◽

Tissue Injury ◽

Inflammatory Diseases ◽

Resolution Of Inflammation ◽

Hematopoietic Stem ◽

Host Disease ◽

Graft Versus Host ◽

Potential Use

Inflammation is an essential reaction of the immune system to infections and sterile tissue injury. However, uncontrolled or unresolved inflammation can cause tissue damage and contribute to the pathogenesis of various inflammatory diseases. Resolution of inflammation is driven by endogenous molecules, known as pro-resolving mediators, that contribute to dampening inflammatory responses, promoting the resolution of inflammation and the recovery of tissue homeostasis. These mediators have been shown to be useful to decrease inflammatory responses and tissue damage in various models of inflammatory diseases. Graft-versus-host disease (GVHD) is a major unwanted reaction following allogeneic hematopoietic stem cell transplantation (allo-HSCT) and is characterized by an exacerbated inflammatory response provoked by antigen disparities between transplant recipient and donor. There is no fully effective treatment or prophylaxis for GVHD. This review explores the effects of several pro-resolving mediators and discusses their potential use as novel therapies in the context of GVHD.

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