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.

Nuclear receptor Nur77: its role in chronic inflammatory diseases

2021 ◽  
Author(s):  
Sanne C. Lith ◽  
Carlie J.M. de Vries
Keyword(s):  
Nuclear Receptor ◽  
Inflammatory Disease ◽  
Inflammatory Responses ◽  
Current Knowledge ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Experimental Models ◽  
Therapeutic Interventions ◽  
Alternative Mechanism ◽  
Signaling Complex

Abstract Nur77 is a nuclear receptor that has been implicated as a regulator of inflammatory disease. The expression of Nur77 increases upon stimulation of immune cells and is differentially expressed in chronically inflamed organs in human and experimental models. Furthermore, in a variety of animal models dedicated to study inflammatory diseases, changes in Nur77 expression alter disease outcome. The available studies comprise a wealth of information on the function of Nur77 in diverse cell types and tissues. Negative cross-talk of Nur77 with the NFκB signaling complex is an example of Nur77 effector function. An alternative mechanism of action has been established, involving Nur77-mediated modulation of metabolism in macrophages as well as in T cells. In this review, we summarize our current knowledge on the role of Nur77 in atherosclerosis, inflammatory bowel disease, multiple sclerosis, rheumatoid arthritis, and sepsis. Detailed insight in the control of inflammatory responses will be essential in order to advance Nur77-targeted therapeutic interventions in inflammatory disease.

scholarly journals Unfulfilled Inflammatory Resolution: A Key Factor in the Pathogenesis of Psoriasis

2020 ◽  
Author(s):  
Zohreh Jadali
Keyword(s):  
Inflammatory Response ◽  
Chronic Inflammation ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Relevant Literature ◽  
Regulatory Mechanisms ◽  
Immune Mediated ◽  
Key Factor ◽  
Inflammation Resolution

Recent literature has highlighted the importance of chronic inflammation in psoriasis pathogenesis. Non-resolving inflammation can trigger progressive tissue damage and inflammatory mediator release which in turn perpetuate the inflammatory cycle. Under normal conditions, inflammatory responses are tightly controlled through several mechanisms that restore normal tissue function and structure. Defects in regulatory mechanisms of the inflammatory response can result in persistent unresolved inflammation and further increases of inflammation. Therefore, this review focuses on defects in regulatory mechanisms of inflammatory responses that lead to uncontrolled chronic inflammation in psoriasis. Databases such as Pubmed Embase, ISI, and Iranian databases including Iranmedex, and SID were researched to identify relevant literature. The results of this review indicate that dysregulation of the inflammatory response may be a likely cause of various immune-mediated inflammatory disorders such as psoriasis. Based on current findings, advances in understanding the cellular and molecular mechanisms involved in inflammation resolution are not only improving our knowledge of the pathogenesis of chronic inflammatory diseases but also supporting the development of new therapeutic strategies.

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

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
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.

scholarly journals Distinct cell death pathways triggered by the adenovirus early region 4 ORF 4 protein

2002 ◽  
Vol 158 (3) ◽  
pp. 519-528 ◽  
Author(s):  
Amélie Robert ◽  
Marie-Joëlle Miron ◽  
Claudia Champagne ◽  
Marie-Claude Gingras ◽  
Philip E. Branton ◽  
...  
Keyword(s):  
Cell Death ◽  
Critical Role ◽  
Adenovirus Type ◽  
Cell Types ◽  
Specific Cell ◽  
Nuclear Targeting ◽  
Early Region ◽  
Delayed Cell Death ◽  
Distinct Cell ◽  
Early Region 4

In transformed cells, induction of apoptosis by adenovirus type 2 (Ad2) early region 4 ORF 4 (E4orf4) correlates with accumulation of E4orf4 in the cell membrane–cytoskeleton fraction. However, E4orf4 is largely expressed in nuclear regions before the onset of apoptosis. To determine the relative contribution of nuclear E4orf4 versus membrane-associated E4orf4 to cell death signaling, we engineered green fluorescent fusion proteins to target E4orf4 to specific cell compartments. The targeting of Ad2 E4orf4 to cell membranes through a CAAX-box or a myristylation consensus signal sufficed to mimic the fast Src-dependent apoptotic program induced by wild-type E4orf4. In marked contrast, the nuclear targeting of E4orf4 abolished the early induction of extranuclear apoptosis. However, nuclear E4orf4 still induced a delayed cell death response independent of Src-like activity and of E4orf4 tyrosine phosphorylation. The zVAD.fmk-inhibitable caspases were dispensable for execution of both cell death programs. Nevertheless, both pathways led to caspase activation in some cell types through the mitochondrial pathway. Finally, our data support a critical role for calpains upstream in the death effector pathway triggered by the Src-mediated cytoplasmic death signal. We conclude that Ad2 E4orf4 induces two distinct cell death responses, whose relative contributions to cell killing may be determined by the genetic background.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals The Role of IL-33 in Host Response toCandida albicans

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
C. Rodríguez-Cerdeira ◽  
A. Lopez-Bárcenas ◽  
B. Sánchez-Blanco ◽  
R. Arenas
Keyword(s):  
Defense Mechanisms ◽  
Fungal Pathogens ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Case Reports ◽  
Pathogenic Fungi ◽  
Cell Types ◽  
Immune Defense ◽  
Beneficial Role

Background. Interleukin (IL) 33 is a recently identified pleiotropic cytokine that influences the activity of multiple cell types and orchestrates complex innate and adaptive immune responses.Methods. We performed an extensive review of the literature published between 2005 and 2013 on IL-33 and related cytokines, their functions, and their regulation of the immune system followingCandida albicanscolonization. Our literature review included cross-references from retrieved articles and specific data from our own studies.Results. IL-33 (IL-1F11) is a recently identified member of the IL-1 family of cytokines. Accumulating evidence suggests a pivotal role of the IL-33/ST2 axis in host immune defense against fungal pathogens, includingC. albicans. IL-33 induces a Th2-type inflammatory response and activates both innate and adaptive immunity. Studies in animal models have shown that Th2 inflammatory responses have a beneficial role in immunity against gastrointestinal and systemic infections byCandidaspp.Conclusions. This review summarizes the most important clinical studies and case reports describing the beneficial role of IL-33 in immunity and host defense mechanisms against pathogenic fungi. The finding that the IL-33/ST2 axis is involved in therapeutic target has implications for the prevention and treatment of inflammatory diseases, including acute or chronic candidiasis.

scholarly journals The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Tao Yu ◽  
Young-Su Yi ◽  
Yanyan Yang ◽  
Jueun Oh ◽  
Deok Jeong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Critical Role ◽  
Biological Response ◽  
Antiviral Defense ◽  
Functional Roles ◽  
Virus Interaction

Inflammation is a complex biological response of tissues to harmful stimuli such as pathogens, cell damage, or irritants. Inflammation is considered to be a major cause of most chronic diseases, especially in more than 100 types of inflammatory diseases which include Alzheimer's disease, rheumatoid arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, hepatitis, and Parkinson's disease. Recently, an increasing number of studies have focused on inflammatory diseases. TBK1 is a serine/threonine-protein kinase which regulates antiviral defense, host-virus interaction, and immunity. It is ubiquitously expressed in mouse stomach, colon, thymus, and liver. Interestingly, high levels of active TBK1 have also been found to be associated with inflammatory diseases, indicating that TBK1 is closely related to inflammatory responses. Even though relatively few studies have addressed the functional roles of TBK1 relating to inflammation, this paper discusses some recent findings that support the critical role of TBK1 in inflammatory diseases and underlie the necessity of trials to develop useful remedies or therapeutics that target TBK1 for the treatment of inflammatory diseases.

scholarly journals Modeling Inflammation in Zebrafish for the Development of Anti-inflammatory Drugs

2021 ◽  
Vol 8 ◽  
Author(s):  
Yufei Xie ◽  
Annemarie H. Meijer ◽  
Marcel J. M. Schaaf
Keyword(s):  
Immune System ◽  
Inflammatory Response ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Model Systems ◽  
Trinitrobenzene Sulfonic Acid ◽  
Inflammatory Drugs ◽  
Anti Inflammatory

Dysregulation of the inflammatory response in humans can lead to various inflammatory diseases, like asthma and rheumatoid arthritis. The innate branch of the immune system, including macrophage and neutrophil functions, plays a critical role in all inflammatory diseases. This part of the immune system is well-conserved between humans and the zebrafish, which has emerged as a powerful animal model for inflammation, because it offers the possibility to image and study inflammatory responses in vivo at the early life stages. This review focuses on different inflammation models established in zebrafish, and how they are being used for the development of novel anti-inflammatory drugs. The most commonly used model is the tail fin amputation model, in which part of the tail fin of a zebrafish larva is clipped. This model has been used to study fundamental aspects of the inflammatory response, like the role of specific signaling pathways, the migration of leukocytes, and the interaction between different immune cells, and has also been used to screen libraries of natural compounds, approved drugs, and well-characterized pathway inhibitors. In other models the inflammation is induced by chemical treatment, such as lipopolysaccharide (LPS), leukotriene B4 (LTB4), and copper, and some chemical-induced models, such as treatment with trinitrobenzene sulfonic acid (TNBS), specifically model inflammation in the gastro-intestinal tract. Two mutant zebrafish lines, carrying a mutation in the hepatocyte growth factor activator inhibitor 1a gene (hai1a) and the cdp-diacylglycerolinositol 3-phosphatidyltransferase (cdipt) gene, show an inflammatory phenotype, and they provide interesting model systems for studying inflammation. These zebrafish inflammation models are often used to study the anti-inflammatory effects of glucocorticoids, to increase our understanding of the mechanism of action of this class of drugs and to develop novel glucocorticoid drugs. In this review, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and to screen for novel anti-inflammatory drugs.

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.

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.

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