scholarly journals Src kinases relax adherens junctions between the neighbors of apoptotic cells to permit apical extrusion

2020 ◽  
Vol 31 (23) ◽  
pp. 2557-2569
Author(s):  
Jessica L. Teo ◽  
Vanesa M. Tomatis ◽  
Luke Coburn ◽  
Anne K. Lagendijk ◽  
Irin-Maya Schouwenaar ◽  
...  
Keyword(s):  
Mechanical Stress ◽  
Apoptotic Cell ◽  
Adherens Junctions ◽  
Apoptotic Cells ◽  
Src Kinases ◽  
Src Family Kinase ◽  
Local Tissue ◽  
Apical Extrusion ◽  
Tissue Stresses ◽  
Cell Extrusion

Apoptotic cell extrusion is predicted to accumulate local tissue stresses that represent a mechanical cost for the epithelium, but how such costs may be alleviated is poorly understood. Here we identify a Src family kinase-mechanosensitive early immediate response of neighbor cells that relieves mechanical stress and allows extrusion to occur.

scholarly journals P115 RhoGEF and microtubules decide the direction apoptotic cells extrude from an epithelium

2009 ◽  
Vol 186 (5) ◽  
pp. 693-702 ◽  
Author(s):  
Gloria Slattum ◽  
Karen M. McGee ◽  
Jody Rosenblatt
Keyword(s):  
Apoptotic Cell ◽  
Extrusion Direction ◽  
Apoptotic Cells ◽  
Epithelial Barrier Function ◽  
Apical Extrusion ◽  
A Cell ◽  
Microtubule Reorientation ◽  
Epithelial Sheet ◽  
P115 Rhogef ◽  
Dying Cells

To preserve epithelial barrier function, dying cells are squeezed out of an epithelium by “apoptotic cell extrusion.” Specifically, a cell destined for apoptosis signals its live neighboring epithelial cells to form and contract a ring of actin and myosin II that squeezes the dying cell out of the epithelial sheet. Although most apoptotic cells extrude apically, we find that some exit basally. Localization of actin and myosin IIA contraction dictates the extrusion direction: basal extrusion requires circumferential contraction of neighboring cells at their apices, whereas apical extrusion also requires downward contraction along the basolateral surfaces. To activate actin/myosin basolaterally, microtubules in neighboring cells reorient and target p115 RhoGEF to this site. Preventing microtubule reorientation restricts contraction to the apex, driving extrusion basally. Extrusion polarity has important implications for tumors where apoptosis is blocked but extrusion is not, as basal extrusion could enable these cells to initiate metastasis.

scholarly journals A unified view of neighbour cell engagement during apoptotic cell extrusion

2020 ◽  
Author(s):  
Kinga Duszyc ◽  
Guillermo A. Gomez ◽  
Anne K. Lagendijk ◽  
Mei-Kwan Yau ◽  
Briony L. Gliddon ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Detection System ◽  
Mechanical Stimulus ◽  
Coincidence Detection ◽  
Apoptotic Cells ◽  
Localized Source ◽  
Apical Extrusion ◽  
Sphingosine 1 Phosphate ◽  
Dependent Signal ◽  
Unified View

AbstractEpithelia must eliminate apoptotic cells to preserve tissue barriers and prevent inflammation [1]. Several different mechanisms exist for apoptotic clearance, including efferocytosis [2, 3] and apical extrusion [4, 5]. We found that extrusion was the first-line response to apoptosis in cultured monolayers and in zebrafish epidermis. During extrusion, the apoptotic cell elicited active lamellipodial protrusions and assembly of a contractile extrusion ring in its neighbours. Depleting E-cadherin compromised both the contractile ring and extrusion, implying that a cadherin-dependent pathway allows apoptotic cells to engage their neighbours for extrusion. We identify RhoA as the cadherin-dependent signal in the neighbour cells and show that it is activated in response to contractile tension from the apoptotic cell. This mechanical stimulus is conveyed by a Myosin VI-dependent mechanotransduction pathway that is necessary both for extrusion and to preserve the epithelial barrier when apoptosis was stimulated. Earlier studies suggested that release of sphingosine-1-phosphate (S1P) from apoptotic cells might define where RhoA was activated. However, we found that although S1P is necessary for extrusion, its contribution does not require a localized source of S1P in the epithelium. We therefore propose a unified view of how RhoA is stimulated to engage neighbour cells for apoptotic extrusion. Here, tension-sensitive mechanotransduction is the proximate mechanism that activates RhoA specifically in the immediate neighbours of apoptotic cells, but this also must be primed by S1P in the tissue environment. Together, these elements provide a coincidence detection system that confers robustness on the extrusion response.

Apoptotic cell extrusion depends on single-cell synthesis of sphingosine-1-phosphate by sphingosine kinase 2

2021 ◽  
Vol 1866 (4) ◽  
pp. 158888
Author(s):  
Bruno Jaime Santacreu ◽  
Daniela Judith Romero ◽  
Lucila Gisele Pescio ◽  
Estefanía Tarallo ◽  
Norma Beatriz Sterin-Speziale ◽  
...  
Keyword(s):  
Single Cell ◽  
Apoptotic Cell ◽  
Sphingosine Kinase ◽  
Sphingosine Kinase 2 ◽  
Sphingosine 1 Phosphate ◽  
Cell Synthesis ◽  
Cell Extrusion

scholarly journals The inflammatory response induced by Pseudomonas aeruginosa in macrophages enhances apoptotic cell removal

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Adriana Valeria Jäger ◽  
Paula Arias ◽  
Maria Virginia Tribulatti ◽  
Marcela Adriana Brocco ◽  
Maria Victoria Pepe ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Pseudomonas Aeruginosa ◽  
Inflammatory Response ◽  
Apoptotic Cell ◽  
Bacterial Pathogen ◽  
Environmental Cues ◽  
Apoptotic Cells ◽  
Phagocytic Function ◽  
Inflammatory Stimulus ◽  
Inflammatory Conditions

AbstractPathogens phagocytosis and the uptake of apoptotic cells (efferocytosis) are essential macrophages tasks, classically considered as mutually exclusive. Macrophages have been observed to polarize into either pro-inflammatory/microbicidal or anti-inflammatory/efferocytic phenotypes. However, macrophage functions have shown to be more complex. Furthermore, little is known about the regulation of efferocytosis under inflammatory conditions. In this study, we elucidate the modulation of the macrophage efferocytic function during an inflammatory stimulus. We find that bone marrow-derived macrophages (BMDM) are very efficient in engulfing both the bacterial pathogen Pseudomonas aeruginosa and apoptotic cells. BMDM showed a high bactericidal capacity unaffected by the concomitant presence of apoptotic material. Plasticity in macrophage programming, in response to changing environmental cues, may modulate efferocytic capability. In this work, we further show that, after phagocyting and processing Pseudomonas aeruginosa, macrophages highly increase their efferocytic capacity without affecting their phagocytic function. Moreover, we demonstrate that Pseudomonas aeruginosa enhances efferocytosis of these phagocytes through the IL-6 signaling pathway. Our results show that the inflammatory response generated by the bacterial processing enhances these macrophages’ capacity to control inflammation through an increased efferocytosis.

scholarly journals Cytotoxicity, Antiproliferative Effects, and Apoptosis Induction of Methanolic Extract ofCynometra caulifloraLinn. Whole Fruit on Human Promyelocytic Leukemia HL-60 Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-6 ◽  
Author(s):  
T-Johari S. A. Tajudin ◽  
Nashriyah Mat ◽  
Abu Bakar Siti-Aishah ◽  
A. Aziz M. Yusran ◽  
Afnani Alwi ◽  
...  
Keyword(s):  
Cell Death ◽  
Methanolic Extract ◽  
Apoptotic Cell ◽  
Mouse Fibroblast ◽  
Promyelocytic Leukemia ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
3T3 Cells ◽  
Nih 3T3 ◽  
Nih 3T3 Cells

Methanolic extract ofCynometra cauliflorawhole fruit was assayed for cytotoxicity against the human promyelocytic leukemia HL-60 and the normal mouse fibroblast NIH/3T3 cell lines by using the MTT assay. The CD50of the extract for 72 hours was 0.9 μg/mL whereas the value for the cytotoxic drug vincristine was 0.2 μg/mL. The viability of the NIH/3T3 cells was at 80.0% when treated at 15.0 μg/mL. The extract inhibited HL-60 cell proliferation with dose dependence. AO/PI staining of HL-60 cells treated with the extract revealed that majority of cells were in the apoptotic cell death mode. Flow cytometry analysis of HL-60 cells treated at CD50of the extract showed that the early apoptotic cells were 31.0, 26.3 and 19.9% at 24, 48, and 72 hours treatment, respectively. The percentage of late apoptotic cells was increased from 62.0 at 24 hours to 64.1 and 70.2 at 48 and 72 hours, respectively. Meanwhile, percent of necrotic cells were 4.9, 6.6, and 8.5 at 24, 48, and 72 hours, respectively. This study has shown that the methanolic extract ofC. cauliflorawhole fruit was cytotoxic towards HL-60 cells and induced the cells into apoptotic cell death mode, but less cytotoxic towards NIH/3T3 cells.

scholarly journals Hydrocortisone decreases apoptosis in jejunum of horses subjected to experimental ischemia and reperfusion

2011 ◽  
Vol 31 (6) ◽  
pp. 471-476 ◽  
Author(s):  
Geraldo Eleno S. Alves ◽  
Heloisa M.F. Mendes ◽  
Tiago G.S. Alves ◽  
Rafael R. Faleiros ◽  
Anilton C. Vasconcelos ◽  
...  
Keyword(s):  
Cell Death ◽  
Time Course ◽  
Apoptotic Cell ◽  
Treated Group ◽  
Apoptotic Cell Death ◽  
Apoptotic Cells ◽  
Ischemia And Reperfusion ◽  
Beneficial Effects ◽  
Time Zero ◽  
Venous Ischemia

In order to evaluate the effect of hydrocortisone on apoptosis in the jejunum of horses subjected to ischemia and reperfusion, ten horses were paired and grouped into two groups - treated (n=5) and non treated (n=5). Segments of the jejunum were used as controls (C), or as venous ischemia (VIsc), which were subjected to 2h of ischemia followed by 2 or 12h of reperfusion. C samples were collected at time zero (prior to ischemia) and VIsc samples were collected at 2h of ischemia and at 2 and 12h of reperfusion. TUNEL positive apoptotic cells were counted in 10 microscopical fields in deep mucosa from each horse throughout the time course. After 12h of reperfusion, the number of apoptotic cells in treated group were significantly lower than in untreated animals, indicating that hydrocortisone inhibits apoptosis. These results indicate that hydrocortisone has a beneficial effects favoring the maintenance of jejunal integrity in horses with ischemia and reperfusion injuries by preventing apoptotic cell death.

scholarly journals Different Roles of a Rat Cortical Thymic Epithelial Cell LineIn Vitroon Thymocytes and Thymocyte Hybridoma Cells: Phagocytosis, Induction of Apoptosis, Nursing and Growth Promoting Activities

2002 ◽  
Vol 9 (2) ◽  
pp. 63-72 ◽  
Author(s):  
Dragana Vucevic ◽  
Miodrag Colic ◽  
Petar Popovic ◽  
Sonja Gašic
Keyword(s):  
Epithelial Cell ◽  
Cell Line ◽  
Apoptotic Cell ◽  
Hybridoma Cells ◽  
Thymic Epithelial Cell ◽  
Apoptotic Cells ◽  
Th Cells ◽  
Nursing Activity ◽  
Induction Of Apoptosis ◽  
Stimulation Of

In this work, the interaction between a rat cortical thymic epithelial cell (TEC) line (R-TNC.1) with nursing activity and thymocytes as well as BWRT 8 thymocyte hybridoma (TH) cells has been studied. The R-TNC.1 cell line significantly bound thymocytes and TH. Binding was stronger during the first 30 min of cell incubation and was followed by a progressive deadhesion. Among adherent thymocytes the proportion of apoptotic cells increased with culture time which was a consequence of higher capacity of the line for binding of apoptotic than viable cells and induction of apoptosis in a subset of adherent thymocytes. Emperiopolesis activity of this thymic nurse cell (TNC) line was manifested by engulfment of thymocytes as well as TH cells. A subset of viable intra-TNC thymocytes has been triggered to die by apoptosis, whereas other internalized thymocytes have been stimulated to proliferate, as measured by an increase in the percentage of cells in mitosis and higher incorporation of bromodeoxyuridine (BrdU), in comparison to thymocytes cultivated alone. A significant stimulation of proliferation of engulfed TH cells was also observed. The R-TNC.1 cell line efficiently phagocytosed both apoptotic thymocytes and TH, and the process is followed by intra-TNC destruction of ingested cells. Cumulatively, these results suggest different role of the R-TNC.1 clone: phagocytosis of apoptotic cells; induction of apoptotic cell death in a subset of both bound and internalized thymocytes and stimulation of proliferation of a subset of intra-TNC thymocytes or TH cells.

Efficient migration of dendritic cells toward lymph node chemokines and induction of TH1 responses require maturation stimulus and apoptotic cell interaction

Blood ◽  
2005 ◽  
Vol 106 (5) ◽  
pp. 1734-1741 ◽  
Author(s):  
Nicolas Bertho ◽  
Henri Adamski ◽  
Louis Toujas ◽  
Martine Debove ◽  
Jean Davoust ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
Lymph Node ◽  
Immune Responses ◽  
Tumor Cells ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Naive T Cells ◽  
Naïve T Cells ◽  
Tnf Α

Abstract Dendritic cells (DCs) have the unique ability to initiate primary immune responses, and they can be conditioned for vaccinal purposes to present antigens after the engulfment of apoptotic cells. To recruit the rare antigen-specific naive T cells, DCs require a maturation step and subsequent transport toward lymph node (LN). To date, prostaglandin E2 (PGE2) is the best-characterized compound inducing this LN-directed migration in vitro, but PGE2 may skew the immune responses in a TH2 direction. We demonstrate here that on incubation with apoptotic tumor cells and tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS), human monocyte-derived DCs become fully mature and acquire high migratory capacities toward LN-directing chemokines. The migration of TNF-α-treated DCs occurs only after cotreatment with apoptotic cells but not with necrotic cells. DC migration requires CD36 expression and incubation with apoptotic cells in the presence of heat-labile serum components. Moreover, on treatment with apoptotic cells and LPS, the migrating DCs are able to recruit naive T cells to generate TH1 immune responses. Our results show that the cotreatment of DCs with apoptotic tumor cells and inflammatory signals is promising for the design of an antitumoral DC-based vaccine. (Blood. 2005;106:1734-1741)

scholarly journals Immunosuppression via adenosine receptor activation by adenosine monophosphate released from apoptotic cells

eLife ◽  
2014 ◽  
Vol 3 ◽  
Author(s):  
Hiroshi Yamaguchi ◽  
Toshihiko Maruyama ◽  
Yoshihiro Urade ◽  
Shigekazu Nagata
Keyword(s):  
Adenosine Receptor ◽  
Molecular Mechanisms ◽  
Apoptotic Cell ◽  
Adenosine Monophosphate ◽  
Receptor Activation ◽  
Death Process ◽  
Apoptotic Cells ◽  
Dependent Manner ◽  
A2a Adenosine Receptor ◽  
Anti Inflammatory

Apoptosis is coupled with recruitment of macrophages for engulfment of dead cells, and with compensatory proliferation of neighboring cells. Yet, this death process is silent, and it does not cause inflammation. The molecular mechanisms underlying anti-inflammatory nature of the apoptotic process remains poorly understood. In this study, we found that the culture supernatant of apoptotic cells activated the macrophages to express anti-inflammatory genes such as Nr4a and Thbs1. A high level of AMP accumulated in the apoptotic cell supernatant in a Pannexin1-dependent manner. A nucleotidase inhibitor and A2a adenosine receptor antagonist inhibited the apoptotic supernatant-induced gene expression, suggesting AMP was metabolized to adenosine by an ecto-5’-nucleotidase expressed on macrophages, to activate the macrophage A2a adenosine receptor. Intraperitoneal injection of zymosan into Adora2a- or Panx1-deficient mice produced high, sustained levels of inflammatory mediators in the peritoneal lavage. These results indicated that AMP from apoptotic cells suppresses inflammation as a ‘calm down’ signal.

scholarly journals Chemokines as phosphatidylserine-bound ‘find-me’ signals in apoptotic cell clearance

2020 ◽  
Author(s):  
Sergio M. Pontejo ◽  
Philip M. Murphy
Keyword(s):  
Extracellular Vesicles ◽  
Chemokine Receptors ◽  
Apoptotic Cell ◽  
Apoptotic Cells ◽  
Anionic Phospholipid ◽  
Apoptotic Cell Clearance ◽  
Cell Clearance ◽  
Cell Plasma ◽  
Signal Activity ◽  
Dying Cells

AbstractChemokines are positively charged cytokines that attract leukocytes by binding to anionic glycosaminoglycans (GAGs) on endothelial cells for efficient presentation to leukocyte G protein-coupled receptors (GPCRs). The atypical chemokine CXCL16 has been reported to also bind the anionic phospholipid phosphatidylserine (PS), but the biological relevance of this interaction remains poorly understood. Here we demonstrate that PS binding is in fact a widely shared property of chemokine superfamily members that, like GAG binding, induces chemokine oligomerization. PS is an essential phospholipid of the inner leaflet of the healthy cell plasma membrane but it is exposed in apoptotic cells to act as an ‘eat-me’ signal that promotes engulfment of dying cells by phagocytes. We found that chemokines can bind PS in pure form as well as in the context of liposomes and on the surface of apoptotic cells and extracellular vesicles released by apoptotic cells, which are known to act as ‘find-me’ signals that chemoattract phagocytes during apoptotic cell clearance. Importantly, we show that GAGs are severely depleted from the surface of apoptotic cells and that extracellular vesicles extracted from apoptotic mouse thymus bind endogenous thymic chemokines and activate cognate chemokine receptors. Together these results indicate that chemokines tethered to surface-exposed PS may be responsible for the chemotactic and find-me signal activity previously attributed to extracellular vesicles, and that PS may substitute for GAGs as the anionic scaffold that regulates chemokine oligomerization and presentation to GPCRs on the GAG-deficient membranes of apoptotic cells and extracellular vesicles. Here, we present a new mechanism by which extracellular vesicles, currently recognized as essential agents for intercellular communication in homeostasis and disease, can transport signaling cytokines.

Sign in / Sign up

Export Citation Format

Share Document