scholarly journals Current Understanding of the Mechanisms for Clearance of Apoptotic Cells—A Fine Balance

2013 ◽  
Vol 6 ◽  
pp. JCD.S11037 ◽  
Author(s):  
Lois A. Hawkins ◽  
Andrew Devitt
Keyword(s):  
Cell Death ◽  
Innate Immune System ◽  
Inflammatory Process ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Apoptotic Cells ◽  
Viable Cells ◽  
Effective Removal ◽  
Multicellular Organisms ◽  
Dying Cells

Apoptosis is an important cell death mechanism by which multicellular organisms remove unwanted cells. It culminates in a rapid, controlled removal of cell corpses by neighboring or recruited viable cells. Whilst many of the molecular mechanisms that mediate corpse clearance are components of the innate immune system, clearance of apoptotic cells is an anti-inflammatory process. Control of cell death is dependent on competing pro-apoptotic and anti-apoptotic signals. Evidence now suggests a similar balance of competing signals is central to the effective removal of cells, through so called ‘eat me’ and ‘don't eat me’ signals. Competing signals are also important for the controlled recruitment of phagocytes to sites of cell death. Consequently recruitment of phagocytes to and from sites of cell death can underlie the resolution or inappropriate propagation of cell death and inflammation. This article highlights our understanding of mechanisms mediating clearance of dying cells and discusses those mechanisms controlling phagocyte migration and how inappropriate control may promote important pathologies.

The final step in programmed cell death: phagocytes carry apoptotic cells to the grave

2003 ◽  
Vol 39 ◽  
pp. 105-117 ◽  
Author(s):  
Aimee M deCathelineau ◽  
Peter M Henson
Keyword(s):  
Cell Death ◽  
Apoptotic Cell ◽  
The Body ◽  
Apoptotic Cells ◽  
Cytokines And Chemokines ◽  
Cell Clearance ◽  
And Function ◽  
Multicellular Organisms ◽  
Dying Cells ◽  
High Degree

As cells undergo apoptosis, they are recognized and removed from the body by phagocytes. This oft-overlooked yet critical final step in the cell-death programme protects tissues from exposure to the toxic contents of dying cells and also serves to prevent further tissue damage by stimulating production of anti-inflammatory cytokines and chemokines. The clearance of apoptotic-cell corpses occurs throughout the lifespan of multicellular organisms and is important for normal development during embryogenesis, the maintenance of normal tissue integrity and function, and the resolution of inflammation. Many of the signal-transduction molecules implicated in the phagocytosis of apoptotic cells appear to have a high degree of evolutionary conservation, and therefore the engulfment of apoptotic cells is likely to represent one of the most primitive forms of phagocytosis. With the realization that the signals that govern apoptotic-cell removal also serve to attenuate inflammation and the immune response, as well as initiate signals for tissue repair and remodelling in response to cell death, the study of apoptotic cell clearance is a field experiencing a dynamic increase in interest and momentum.

scholarly journals Current and Emerging Biomarkers of Cell Death in Human Disease

2014 ◽  
Vol 2014 ◽  
pp. 1-10 ◽  
Author(s):  
Kongning Li ◽  
Deng Wu ◽  
Xi Chen ◽  
Ting Zhang ◽  
Lu Zhang ◽  
...  
Keyword(s):  
Cell Death ◽  
Molecular Mechanisms ◽  
Research Area ◽  
Human Diseases ◽  
Mitotic Catastrophe ◽  
Regulated Necrosis ◽  
Early Diagnose ◽  
Multicellular Organisms ◽  
The Relationship ◽  
Made In

Cell death is a critical biological process, serving many important functions within multicellular organisms. Aberrations in cell death can contribute to the pathology of human diseases. Significant progress made in the research area enormously speeds up our understanding of the biochemical and molecular mechanisms of cell death. According to the distinct morphological and biochemical characteristics, cell death can be triggered by extrinsic or intrinsic apoptosis, regulated necrosis, autophagic cell death, and mitotic catastrophe. Nevertheless, the realization that all of these efforts seek to pursue an effective treatment and cure for the disease has spurred a significant interest in the development of promising biomarkers of cell death to early diagnose disease and accurately predict disease progression and outcome. In this review, we summarize recent knowledge about cell death, survey current and emerging biomarkers of cell death, and discuss the relationship with human diseases.

scholarly journals Caspase Activity Is Required for Engulfment of Apoptotic Cells

2013 ◽  
Vol 33 (16) ◽  
pp. 3191-3201 ◽  
Author(s):  
Boris Shklyar ◽  
Flonia Levy-Adam ◽  
Ketty Mishnaevski ◽  
Estee Kurant
Keyword(s):  
Central Nervous System ◽  
Normal Development ◽  
Function Analysis ◽  
Living Cells ◽  
Apoptotic Cells ◽  
Caspase Activity ◽  
Internal Inhibition ◽  
Content Type ◽  
Multicellular Organisms ◽  
Dying Cells

Clearance of apoptotic cells by phagocytic neighbors is crucial for normal development of multicellular organisms. However, how phagocytes discriminate between healthy and dying cells remains poorly understood. We focus on glial phagocytosis of apoptotic neurons during development of theDrosophilacentral nervous system. We identified phosphatidylserine (PS) as a ligand on apoptotic cells for the phagocytic receptor Six Microns Under (SIMU) and report that PS alone is not sufficient for engulfment. Our data reveal that, additionally to PS exposure, caspase activity is required for clearance of apoptotic cells by phagocytes. Here we demonstrate that SIMU recognizes and binds PS on apoptotic cells through its N-terminal EMILIN (EMI), Nimrod 1 (NIM1), and NIM2 repeats, whereas the C-terminal NIM3 and NIM4 repeats control SIMU affinity to PS. Based on the structure-function analysis of SIMU, we discovered a novel mechanism of internal inhibition responsible for differential affinities of SIMU to its ligand which might prevent elimination of living cells exposing PS on their surfaces.

scholarly journals Activation of NLRP3 and AIM2 Inflammasomes by Porphyromonas gingivalis Infection

2013 ◽  
Vol 82 (1) ◽  
pp. 112-123 ◽  
Author(s):  
Eunjoo Park ◽  
Hee Sam Na ◽  
Yu-Ri Song ◽  
Seong Yeol Shin ◽  
You-Me Kim ◽  
...  
Keyword(s):  
Cell Death ◽  
Porphyromonas Gingivalis ◽  
Molecular Mechanisms ◽  
Atp Release ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Innate Immune Responses ◽  
Content Type ◽  
Periodontal Destruction ◽  
Tlr4 Activation

ABSTRACTPorphyromonas gingivalis, a major periodontopathogen, is involved in the pathogenesis of periodontitis. Interleukin-1β (IL-1β), a proinflammatory cytokine, regulates innate immune responses and is critical for the host defense against bacterial infection. However, excessive IL-1β is linked to periodontal destruction. IL-1β synthesis, maturation, and secretion are tightly regulated by Toll-like receptor (TLR) signaling and inflammasome activation. We found much higher levels of inflammasome components in the gingival tissues from patients with chronic periodontitis than in those from healthy controls. To investigate the molecular mechanisms by whichP. gingivalisinfection causes IL-1β secretion, we examined the characteristics ofP. gingivalis-induced signaling in differentiated THP-1 cells. We found thatP. gingivalisinduces IL-1β secretion and inflammatory cell death via caspase-1 activation. We also found thatP. gingivalis-induced IL-1β secretion and pyroptic cell death required both NLRP3 and AIM2 inflammasome activation. The activation of the NLRP3 inflammasome was mediated by ATP release, the P2X7receptor, and lysosomal damage. In addition, we found that the priming signal via TLR2 and TLR4 activation precedesP. gingivalis-induced IL-1β release. Our study provides novel insight into the innate immune response againstP. gingivalisinfection which could potentially be used for the prevention and therapy of periodontitis.

scholarly journals “Dead Cells Talking”: The Silent Form of Cell Death Is Not so Quiet

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Richard Jäger ◽  
Howard O. Fearnhead
Keyword(s):  
Cell Death ◽  
Cancer Therapy ◽  
Apoptotic Cell ◽  
Surrounding Tissue ◽  
Apoptotic Cells ◽  
Cancer Cell Proliferation ◽  
Loss Of Function ◽  
Molecular Events ◽  
Dying Cells

After more than twenty years of research, the molecular events of apoptotic cell death can be succinctly stated; different pathways, activated by diverse signals, increase the activity of proteases called caspases that rapidly and irreversibly dismantle condemned cell by cleaving specific substrates. In this time the ideas that apoptosis protects us from tumourigenesis and that cancer chemotherapy works by inducing apoptosis also emerged. Currently, apoptosis research is shifting away from the intracellular events within the dying cell to focus on the effect of apoptotic cells on surrounding tissues. This is producing counterintuitive data showing that our understanding of the role of apoptosis in tumourigenesis and cancer therapy is too simple, with some interesting and provocative implications. Here, we will consider evidence supporting the idea that dying cells signal their presence to the surrounding tissue and, in doing so, elicit repair and regeneration that compensates for any loss of function caused by cell death. We will discuss evidence suggesting that cancer cell proliferation may be driven by inappropriate or corrupted tissue-repair programmes that are initiated by signals from apoptotic cells and show how this may dramatically modify how we view the role of apoptosis in both tumourigenesis and cancer therapy.

scholarly journals The IκB-Protein BCL-3 Controls MAPK Activity by Promoting TPL-2 Degradation in the Nucleus

2018 ◽  
Author(s):  
Patricia E. Collins ◽  
Domenico Somma ◽  
David Kerrigan ◽  
Felicity Herrington ◽  
Karen R. Keeshan ◽  
...  
Keyword(s):  
Immune Cells ◽  
Innate Immune System ◽  
Molecular Mechanisms ◽  
Primary Site ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Nucleocytoplasmic Shuttling ◽  
Activation Threshold ◽  
Invasive Pathogens ◽  
Mapk Activity

AbstractThe ability of the innate immune system to distinguish between low level microbial presence and invasive pathogens is fundamental for immune homeostasis and immunity. However, the molecular mechanisms underlying threat discrimination by innate immune cells are not clearly defined. Here we describe the integration of the NF-ĸB and MAPK pathways in the nucleus by the IĸB protein BCL-3 and the MAP3K TPL-2. Our data reveals that TPL-2 is a nucleocytoplasmic shuttling protein and demonstrates that the nucleus is the primary site for TPL-2 ubiquitination and proteasomal degradation. BCL-3 promotes TPL-2 degradation through interaction in the nucleus. As a consequence, Bcl3-/- macrophages have increased TPL-2 stability and MAPK activity following TLR stimulation. The enhanced stability of TPL-2 in Bcl3-/- macrophages lowers the MAPK activation threshold and the level of TLR ligand required to initiate an inflammatory response. This study establishes the nucleus as a key regulatory site for TLR-induced MAPK activity and identifies BCL-3 as a regulator of the cellular decision to initiate inflammation

scholarly journals A Novel Regulatory Player in the Innate Immune System: Long Non-Coding RNAs

2021 ◽  
Vol 22 (17) ◽  
pp. 9535
Author(s):  
Yuhuai Xie ◽  
Yuanyuan Wei
Keyword(s):  
Immune System ◽  
Immune Cells ◽  
Innate Immune System ◽  
Molecular Mechanisms ◽  
Innate Immune ◽  
Innate Immune Cells ◽  
Immune Mediated ◽  
Development And Differentiation ◽  
Non Coding Rnas ◽  
And Function

Long non-coding RNAs (lncRNAs) represent crucial transcriptional and post-transcriptional gene regulators during antimicrobial responses in the host innate immune system. Studies have shown that lncRNAs are expressed in a highly tissue- and cell-specific- manner and are involved in the differentiation and function of innate immune cells, as well as inflammatory and antiviral processes, through versatile molecular mechanisms. These lncRNAs function via the interactions with DNA, RNA, or protein in either cis or trans pattern, relying on their specific sequences or their transcriptions and processing. The dysregulation of lncRNA function is associated with various human non-infectious diseases, such as inflammatory bowel disease, cardiovascular diseases, and diabetes mellitus. Here, we provide an overview of the regulation and mechanisms of lncRNA function in the development and differentiation of innate immune cells, and during the activation or repression of innate immune responses. These elucidations might be beneficial for the development of therapeutic strategies targeting inflammatory and innate immune-mediated diseases.

scholarly journals Caspases in Cell Death, Inflammation, and Pyroptosis

2020 ◽  
Vol 38 (1) ◽  
pp. 567-595 ◽  
Author(s):  
Sannula Kesavardhana ◽  
R.K. Subbarao Malireddi ◽  
Thirumala-Devi Kanneganti
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Immune Responses ◽  
Cross Talk ◽  
Cysteine Proteases ◽  
Proteolytic Processing ◽  
Innate Immune ◽  
Innate Immune Responses ◽  
New Research ◽  
Multicellular Organisms

Caspases are a family of conserved cysteine proteases that play key roles in programmed cell death and inflammation. In multicellular organisms, caspases are activated via macromolecular signaling complexes that bring inactive procaspases together and promote their proximity-induced autoactivation and proteolytic processing. Activation of caspases ultimately results in programmed execution of cell death, and the nature of this cell death is determined by the specific caspases involved. Pioneering new research has unraveled distinct roles and cross talk of caspases in the regulation of programmed cell death, inflammation, and innate immune responses. In-depth understanding of these mechanisms is essential to foster the development of precise therapeutic targets to treat autoinflammatory disorders, infectious diseases, and cancer. This review focuses on mechanisms governing caspase activation and programmed cell death with special emphasis on the recent progress in caspase cross talk and caspase-driven gasdermin D–induced pyroptosis.

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