Academic literature on the topic 'Efferocytose'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the lists of relevant articles, books, theses, conference reports, and other scholarly sources on the topic 'Efferocytose.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Journal articles on the topic "Efferocytose"
1
Larson, Sandy R., Stacey Thomas, Shaikh M. Atif, Sophie Gibbings, Miglena Prabagar, Peter M. Henson, and Claudia Jakubzick. "Ly6C+ monocyte efferocytosis and cross-presentation of cell-associated antigen." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 116.12. http://dx.doi.org/10.4049/jimmunol.196.supp.116.12.
Full textAbstract:
Abstract Recently it was shown that circulating Ly6C+ monocytes traffic from tissue to the draining lymph nodes (LNs) with minimal alteration in their overall phenotype. Furthermore, in the steady state, Ly6C+ monocytes are as abundant as classical dendritic cells (DCs) within the draining LNs, and even more abundant during inflammation. However, little is known about the functional roles of constitutively trafficking Ly6C+ monocytes. In this study we investigated whether Ly6C+ monocytes can efferocytose (acquire dying cells) and cross-present cell-associated antigen, a functional property specially attributed to Batf3+ DCs. We demonstrated that Ly6C+ monocytes intrinsically efferocytose and cross-present cell-associated antigen to CD8+ T cells. In addition, efferocytosis was enhanced upon direct activation of the Ly6C+ monocytes through its corresponding TLRs, TLR4 and TLR7. However, only ligation of TLR7, and not TLR4, enhanced cross-presentation by Ly6C+ monocytes. Overall, this study outlines two functional roles, among others, that Ly6C+ monocytes have during an adaptive immune response.
2
Vetter, Mathieu, and Philippe Saas. "« Fort comme la mort », où comment l’efferocytose contrôle la résolution de l’inflammation." médecine/sciences 40, no. 5 (May 2024): 428–36. http://dx.doi.org/10.1051/medsci/2024050.
Full textAbstract:
L’arrêt de la réponse inflammatoire, ou résolution de l’inflammation, est considéré aujourd’hui comme un processus actif lié à la production (ou à la libération) de composés anti-inflammatoires aussi appelés composés pro-résolutifs. L’évènement permettant d’enclencher la résolution de l’inflammation est l’élimination des cellules immunitaires apoptotiques par les macrophages, un processus nommé efferocytose, dont l’altération est à l’origine de différentes maladies. Dans cette synthèse, nous décrivons les étapes de cette efferocytose et les mécanismes qui en résultent et permettent de stopper l’inflammation. Nous évoquerons également de nouvelles pistes thérapeutiques fondées sur les facteurs pro-résolutifs : la thérapie résolutive.
3
Higham, Andrew, Tom Scott, Jian Li, Rosemary Gaskell, Aisha Baba Dikwa, Rajesh Shah, M. Angeles Montero-Fernandez, Simon Lea, and Dave Singh. "Effects of corticosteroids on COPD lung macrophage phenotype and function." Clinical Science 134, no. 7 (April 2020): 751–63. http://dx.doi.org/10.1042/cs20191202.
Full textAbstract:
Abstract The numbers of macrophages are increased in the lungs of chronic obstructive pulmonary disease (COPD) patients. COPD lung macrophages have reduced ability to phagocytose microbes and efferocytose apoptotic cells. Inhaled corticosteroids (ICSs) are widely used anti-inflammatory drugs in COPD; however, their role beyond suppression of cytokine release has not been explored in COPD macrophages. We have examined the effects of corticosteroids on COPD lung macrophage phenotype and function. Lung macrophages from controls and COPD patients were treated with corticosteroids; effects on gene and protein expression of CD163, CD164, CD206, MERTK, CD64, CD80 and CD86 were studied. We also examined the effect of corticosteroids on the function of CD163, MERTK and cluster of differentiation 64 (CD64). Corticosteroid increased CD163, CD164, CD206 and MERTK expression and reduced CD64, CD80 and CD86 expression. We also observed an increase in the uptake of the haemoglobin–haptoglobin complex (CD163) from 59 up to 81% and an increase in efferocytosis of apoptotic neutrophils (MERTK) from 15 up to 28% following corticosteroid treatment. We observed no effect on bacterial phagocytosis. Corticosteroids alter the phenotype and function of COPD lung macrophages. Our findings suggest mechanisms by which corticosteroids exert therapeutic benefit in COPD, reducing iron available for bacterial growth and enhancing efferocytosis.
4
Lam, Austin Le, and Bryan Heit. "Having an Old Friend for Dinner: The Interplay between Apoptotic Cells and Efferocytes." Cells 10, no. 5 (May 20, 2021): 1265. http://dx.doi.org/10.3390/cells10051265.
Full textAbstract:
Apoptosis, the programmed and intentional death of senescent, damaged, or otherwise superfluous cells, is the natural end-point for most cells within multicellular organisms. Apoptotic cells are not inherently damaging, but if left unattended, they can lyse through secondary necrosis. The resulting release of intracellular contents drives inflammation in the surrounding tissue and can lead to autoimmunity. These negative consequences of secondary necrosis are avoided by efferocytosis—the phagocytic clearance of apoptotic cells. Efferocytosis is a product of both apoptotic cells and efferocyte mechanisms, which cooperate to ensure the rapid and complete removal of apoptotic cells. Herein, we review the processes used by apoptotic cells to ensure their timely removal, and the receptors, signaling, and cellular processes used by efferocytes for efferocytosis, with a focus on the receptors and signaling driving this process.
5
Aitcheson, Savannah M., Francesca D. Frentiu, Sheree E. Hurn, Katie Edwards, and Rachael Z. Murray. "Skin Wound Healing: Normal Macrophage Function and Macrophage Dysfunction in Diabetic Wounds." Molecules 26, no. 16 (August 13, 2021): 4917. http://dx.doi.org/10.3390/molecules26164917.
Full textAbstract:
Macrophages play a prominent role in wound healing. In the early stages, they promote inflammation and remove pathogens, wound debris, and cells that have apoptosed. Later in the repair process, they dampen inflammation and secrete factors that regulate the proliferation, differentiation, and migration of keratinocytes, fibroblasts, and endothelial cells, leading to neovascularisation and wound closure. The macrophages that coordinate this repair process are complex: they originate from different sources and have distinct phenotypes with diverse functions that act at various times in the repair process. Macrophages in individuals with diabetes are altered, displaying hyperresponsiveness to inflammatory stimulants and increased secretion of pro-inflammatory cytokines. They also have a reduced ability to phagocytose pathogens and efferocytose cells that have undergone apoptosis. This leads to a reduced capacity to remove pathogens and, as efferocytosis is a trigger for their phenotypic switch, it reduces the number of M2 reparative macrophages in the wound. This can lead to diabetic foot ulcers (DFUs) forming and contributes to their increased risk of not healing and becoming infected, and potentially, amputation. Understanding macrophage dysregulation in DFUs and how these cells might be altered, along with the associated inflammation, will ultimately allow for better therapies that might complement current treatment and increase DFU’s healing rates.
6
Myers, Kayla V., Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, and Kenneth J. Pienta. "Abstract 2546: Targeting MerTK-mediated efferocytosis in the prostate cancer TME." Cancer Research 82, no. 12_Supplement (June 15, 2022): 2546. http://dx.doi.org/10.1158/1538-7445.am2022-2546.
Full textAbstract:
Abstract The prostate cancer tumor microenvironment (TME) is comprised of many different components and cell types that influence tumor progression and patient outcome. Macrophages are highly abundant immune cells in the prostate cancer TME. Macrophage phenotypes can be modeled on a continuous spectrum of M1-like (anti-tumor macrophages) to M2-like (pro-tumor macrophages) and most macrophages in the prostate cancer TME are M2-like. Efferocytosis, the phagocytosis of apoptotic cells, is a pro-tumor function of M2-like macrophages. We have developed a flow cytometry assay to quantify efferocytosis of the prostate cancer cell line LNCaP. With both cell line-based THP-1 macrophages and human monocyte-derived macrophages (HMDMs), we observe that M2 macrophages efferocytose LNCaP cells more than M1 macrophages. Based on literature from other models and contexts, efferocytosis further supports the M2-like phenotype. Efferocytosis also prevents the apoptotic cell from progressing to secondary necrosis, which would attract an M1-like macrophage phenotype. Due these aspects, we hypothesize efferocytosis in the prostate cancer TME is a tumor-promoting function of macrophages. Following efferocytosis of LNCaP cells by M2 HMDMs, we detect a decrease in the M1-like, anti-tumor marker CD80 and an increase in M2-like, pro-tumor markers CD206 and PDL1. Due to this role in modulating macrophage phenotype, we hypothesize targeting efferocytosis will slow prostate cancer growth and promote an anti-tumor immune infiltrate, including M1-like macrophages. MerTK is a receptor tyrosine kinase that mediates efferocytosis by binding phosphatidylserine on apoptotic cells. At both the protein and mRNA level, we detect higher MerTK expression in M2 than M1 THP-1 macrophages and HMDMs. Upon addition of apoptotic LNCaP cells, we observe an increase in phosphorylated MerTK (active form), suggesting the role of MerTK in prostate cancer cell efferocytosis. Currently, we are targeting MerTK to block prostate cancer cell efferocytosis in vitro and in vivo. We have generated a Mertk-/-, Hi-Myc mouse model on the FVB/N background. This prostate cancer GEMM will be used to assess the role of MerTK across different stages of prostate cancer progression. We will be comparing tumor size and immune infiltration between Mertk+/+ and Mertk-/- Hi-Myc mice aged to 2 months, 6 months and 12 months. We predict that the Mertk-/- mice will have smaller tumors and an overall anti-tumor immune infiltrate compared to Mertk+/+ mice in this model due to lack of efferocytosis. Citation Format: Kayla V. Myers, Amber E. de Groot, Anna L. Gonye, Luke V. Loftus, Sarah R. Amend, Kenneth J. Pienta. Targeting MerTK-mediated efferocytosis in the prostate cancer TME [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2546.
7
Banerjee, Somenath, Jagdish C. Joshi, Vijayalakshmi Yalagala, and Dolly Mehta. "Loss of myeloid S1PR1 makes dysfunctional alveolar macrophages and vascular injury by inducing myeloid bias." Journal of Immunology 206, no. 1_Supplement (May 1, 2021): 112.17. http://dx.doi.org/10.4049/jimmunol.206.supp.112.17.
Full textAbstract:
Abstract Alveolar macrophages (AM) are the most abundant resident innate immune cells in the lungs and directly communicate with both the non-sterile external environment and the pulmonary epithelium. AM initially trigger protective inflammation upon sensing pathogen but later induce lung repair by clearing dead cells, known as efferocytosis, and dampening of inflammation. Studies show that monocytes recruited in the airspace during injury gain AM signature and contribute in lung repair. Sphingosine 1 phosphate receptor 1 (S1PR1), is widely studied in lung endothelium as a barrier protective mechanism and in immune cells in context of trafficking and inflammation but has not yet extensively studied in respect to origin and function of AM. Here, we deleted S1PR1 in mice by crossing S1PR1f/f with LysMCre (S1PR1ΔLyz) mice to investigate the role of S1PR1 in myeloid cells in the mechanism of lung injury. We show that loss of S1PR1 in myeloid cells of mice (S1PR1ΔLyz mice) has 3-fold higher AM pool but surprisingly these mice showed defective lung fluid balance basally or post LPS challenge (intratracheal 0.5 mg/kg). We found that S1PR1−/−AM produced markedly less pro-inflammatory cytokines (IL1b and TNFa) and could not efferocytose. Intriguingly, S1PR1 deficiency induced myeloid biased haematopoiesis as evident from less erythroid progenitor (~0.75 fold) and B cells (~0.82 fold) in bone marrow of S1PR1ΔLyz mice leading to increased circulating monocytes. panRNAseq of S1PR1−/− AM showed markedly reduced Sphk1 and NFκB1 expression and increased expression of KLF4, Myb, Myc, TLR7 & 8. These findings indicate that loss of S1PR1 misfires the generation of incompetent monocytes leading to dysfunctional AM and defective lung repair.
8
Abbasi, Muddasir H., Nimra Shehzadi, Arooj Safdar, Rabia Aslam, Arsha Tariq, Misbah Shahid, Azka Zafar, Nadeem Sheikh, and Muhammad Babar Khawar. "Role of Efferocytosis in Health and Diseases." Albus Scientia 2024, no. 1 (May 18, 2024): 1–12. http://dx.doi.org/10.56512/as.2024.1.e240518.
Full textAbstract:
Efferocytosis is the process of removal of apoptotic cells through phagocytosis by the specialized cells known as efferocytes. Clearance of dead cells also plays an important role in the defensive system of organisms as efferocytosis maintains homeostasis and repairing of tissues and organs. In this process, the dying cell releases signals for identification and engulfment which is further processed by macrophages. Efferocytosis prevents the secondary necrosis and release of pro-inflammatory cellular contents. This clearance process involves interplay of signaling molecules, receptors, and other mediators that ensures prompt recognitions and removal of dying cells. Dysregulation of efferocytosis has been implicated in various pathological conditions, including autoimmune diseases, chronic inflammation, and atherosclerosis. This review focuses on some common autoimmune diseases, cardiovascular diseases, respiratory disorders, and neurodegenerative disorders due to impaired efferocytosis. To describe the pathophysiology of efferocytosis in diseases more extensive studies are required.
9
Li, Vivien, Michele D. Binder, and Trevor J. Kilpatrick. "The Tolerogenic Influence of Dexamethasone on Dendritic Cells Is Accompanied by the Induction of Efferocytosis, Promoted by MERTK." International Journal of Molecular Sciences 24, no. 21 (November 2, 2023): 15903. http://dx.doi.org/10.3390/ijms242115903.
Full textAbstract:
Many treatments for autoimmune diseases, caused by the loss of immune self-tolerance, are broadly immunosuppressive. Dendritic cells (DCs) can be induced to develop anti-inflammatory/tolerogenic properties to suppress aberrant self-directed immunity by promoting immune tolerance in an antigen-specific manner. Dexamethasone can generate tolerogenic DCs and upregulates MERTK expression. As MERTK can inhibit inflammation, we investigated whether dexamethasone’s tolerogenic effects are mediated via MERTK, potentially providing a novel therapeutic approach. Monocyte-derived DCs were treated with dexamethasone, and with and without MERTK ligands or MERTK inhibitors. Flow cytometry was used to assess effects of MERTK modulation on co-stimulatory molecule expression, efferocytosis, cytokine secretion and T cell proliferation. The influence on expression of Rab17, which coordinates the diversion of efferocytosed material away from cell surface presentation, was assessed. Dexamethasone-treated DCs had upregulated MERTK expression, decreased expression of co-stimulatory molecules, maturation and proliferation of co-cultured T cells and increased uptake of myelin debris. MERTK ligands did not potentiate these properties, whilst specific MERTK inhibition only reversed dexamethasone’s effect on myelin uptake. Cells undergoing efferocytosis had higher Rab17 expression. Dexamethasone-enhanced efferocytosis in DCs is MERTK-dependent and could exert its tolerogenic effects by increasing Rab17 expression to prevent the presentation of efferocytosed material on the cell surface to activate adaptive immune responses.
10
Poe, S. L., M. Arora, T. B. Oriss, M. Yarlagadda, K. Isse, A. Khare, D. E. Levy, et al. "STAT1-regulated lung MDSC-like cells produce IL-10 and efferocytose apoptotic neutrophils with relevance in resolution of bacterial pneumonia." Mucosal Immunology 6, no. 1 (July 11, 2012): 189–99. http://dx.doi.org/10.1038/mi.2012.62.
Full textDissertations / Theses on the topic "Efferocytose"
1
Viaud, Manon. "Contrôle métabolique de la production et de la clairance des monocytes dans les pathologies inflammatoires." Electronic Thesis or Diss., Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4033.
Full textAbstract:
La myélopoïèse est finement régulée au niveau métabolique. Les cellules myéloïdes (monocytes et macrophages) sont au centre de nombreuses pathologies. Ma thèse étudie le rôle du métabolisme des cellules myéloïdes dans les pathologies inflammatoires. Je me suis intéressée au métabolisme du cholestérol dans la prolifération anarchique des monocytes (cancérisation) et j’ai étudié des mutations du transporteur ABCA1 (ATP-Binding Cassette A1) impliqué dans l’efflux de cholestérol, qui sont à l’origine d’une prolifération accrue des monocytes, soulignant l’impact du métabolisme lipidique dans la régulation de la prolifération cellulaire. Le métabolisme du glucose est lui aussi impliqué dans la régulation de la myélopoïèse. Nous avons étudié le rôle du transporteur au glucose, Glut-1, dans l’athérosclérose, qui est une pathologie inflammatoire chronique. Dans ce contexte, les CSH et les progéniteurs myéloïdes sur-expriment le transporteur Glut-1, induisant une monocytose, permettant l’accumulation de macrophages dans les lésions. La déficience en Glut-1 prévient la monocytose et le développement des plaques d’athérosclérose. Je me suis intéressée au rôle de la lipase acide lysosomale (LIPA) dans la phagocytose des cellules apoptotiques (efferocytose) par les macrophages, où une grande quantité de cholestérol ingérée doit être dégradée. LIPA en est un acteur central. L’inhibition de cette enzyme provoque un stress oxydatif mitochondrial, et active l’inflammasome NLRP3, contribuant à une inflammation chronique. Cela réduit aussi l’activation des Liver-X-Receptor et induit un défaut d’efferocytose des macrophages, ce qui participe à l’apparition d’une inflammatoire chroniqueMyeloid cells are produced by hematopoiesis, from hematopoietic stem cells (HSCs), a metabolically fine-tuned process. In chronic inflammatory diseases, an increased amount of monocytes is observed (monocytosis). My thesis focuses on the role of myeloid cells metabolism in chronic inflammatory diseases. We focused on the impact of cholesterol metabolism alterations into the anarchic proliferation of monocytes (carcinogenesis). Novel somatic mutations in the cholesterol efflux transporter ATP-Binding Cassette A1 induce carcinogenesis of monocytes, highlighting the impact of cholesterol efflux pathway in monocyte proliferation. I studied glycolysis in atherosclerosis, a chronic inflammatory disease. HSCs and myeloid progenitors exhibited higher Glut-1 expression in a murine model of atherosclerosis, with an enhanced accumulation of macrophages into lesions. A partial deletion of Glut-1 reduced HSCs and progenitors proliferation, limiting monocytosis and atherosclerotic plaques development. I studied the role of lysosomal acid lipase (LIPA) in the phagocytosis of apoptotic cells (efferocytosis). When a macrophage phagocytized an apoptotic cell, an important amount of cholesterol has to be degraded. LIPA is a key player in this process. When LIPA is inhibited, we observed a reduced production of 25- and 27-hydroxycholesterol, leading to an increased mitochondrial oxidative stress, which activated NLRP3 inflammasome activation and a reduced LXR activation. LIPA inhibition leads to a defective efferocytosis in vitro and in vivo. LIPA enzyme is essential to prevent metabolic inflammation by maintaining effective efferocytosis
2
Viaud, Manon. "Contrôle métabolique de la production et de la clairance des monocytes dans les pathologies inflammatoires." Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4033/document.
Full textAbstract:
La myélopoïèse est finement régulée au niveau métabolique. Les cellules myéloïdes (monocytes et macrophages) sont au centre de nombreuses pathologies. Ma thèse étudie le rôle du métabolisme des cellules myéloïdes dans les pathologies inflammatoires. Je me suis intéressée au métabolisme du cholestérol dans la prolifération anarchique des monocytes (cancérisation) et j’ai étudié des mutations du transporteur ABCA1 (ATP-Binding Cassette A1) impliqué dans l’efflux de cholestérol, qui sont à l’origine d’une prolifération accrue des monocytes, soulignant l’impact du métabolisme lipidique dans la régulation de la prolifération cellulaire. Le métabolisme du glucose est lui aussi impliqué dans la régulation de la myélopoïèse. Nous avons étudié le rôle du transporteur au glucose, Glut-1, dans l’athérosclérose, qui est une pathologie inflammatoire chronique. Dans ce contexte, les CSH et les progéniteurs myéloïdes sur-expriment le transporteur Glut-1, induisant une monocytose, permettant l’accumulation de macrophages dans les lésions. La déficience en Glut-1 prévient la monocytose et le développement des plaques d’athérosclérose. Je me suis intéressée au rôle de la lipase acide lysosomale (LIPA) dans la phagocytose des cellules apoptotiques (efferocytose) par les macrophages, où une grande quantité de cholestérol ingérée doit être dégradée. LIPA en est un acteur central. L’inhibition de cette enzyme provoque un stress oxydatif mitochondrial, et active l’inflammasome NLRP3, contribuant à une inflammation chronique. Cela réduit aussi l’activation des Liver-X-Receptor et induit un défaut d’efferocytose des macrophages, ce qui participe à l’apparition d’une inflammatoire chroniqueMyeloid cells are produced by hematopoiesis, from hematopoietic stem cells (HSCs), a metabolically fine-tuned process. In chronic inflammatory diseases, an increased amount of monocytes is observed (monocytosis). My thesis focuses on the role of myeloid cells metabolism in chronic inflammatory diseases. We focused on the impact of cholesterol metabolism alterations into the anarchic proliferation of monocytes (carcinogenesis). Novel somatic mutations in the cholesterol efflux transporter ATP-Binding Cassette A1 induce carcinogenesis of monocytes, highlighting the impact of cholesterol efflux pathway in monocyte proliferation. I studied glycolysis in atherosclerosis, a chronic inflammatory disease. HSCs and myeloid progenitors exhibited higher Glut-1 expression in a murine model of atherosclerosis, with an enhanced accumulation of macrophages into lesions. A partial deletion of Glut-1 reduced HSCs and progenitors proliferation, limiting monocytosis and atherosclerotic plaques development. I studied the role of lysosomal acid lipase (LIPA) in the phagocytosis of apoptotic cells (efferocytosis). When a macrophage phagocytized an apoptotic cell, an important amount of cholesterol has to be degraded. LIPA is a key player in this process. When LIPA is inhibited, we observed a reduced production of 25- and 27-hydroxycholesterol, leading to an increased mitochondrial oxidative stress, which activated NLRP3 inflammasome activation and a reduced LXR activation. LIPA inhibition leads to a defective efferocytosis in vitro and in vivo. LIPA enzyme is essential to prevent metabolic inflammation by maintaining effective efferocytosis
3
Millet, Arnaud. "Rôle pro-inflammatoire et immunomodulateur de la proteinase 3 membranaire exprimée au cours de l'apoptose : implications dans la granulomatose avec polyangéite." Phd thesis, Université René Descartes - Paris V, 2014. http://tel.archives-ouvertes.fr/tel-00940917.
Full textAbstract:
La granulomatose avec polyangéite est une vascularite systémique associée à une réaction auto-immune dirigée contre la protéinase 3, une serine protéase du neutrophile. Cette protéine présente un profil particulier d'expression dans le neutrophile, caractérisé notamment par une expression membranaire au cours de l'apoptose. Cette capacité de la protéinase 3 à se lier aux membranes repose sur l'existence de quatre acides amines formant un patch hydrophobe. Cette expression membranaire au cours de l'apoptose, qui dépend de l'existence de ce patch hydrophobe, conduit la protéinase 3 à interagir avec la calréticuline qui est une molécule impliquée dans la reconnaissance des cellules apopotiques par les macrophages. Nous avons démontré que cette interaction conduit la protéinase 3 à modifier le phénotype pro-résolutif des macrophages consécutif à la phagocytose de cellules apoptotiques. Le phénotype pro-inflammatoire résultant de cette expression de la protéinase 3 dépend de la voie de signalisation MyD88 mimant un signal danger. Cette activation des macrophages conduit à la sécrétion de chimiokines (MCP-1, KC, MIP-1α et MIP-1β) impliquées dans le recrutement de cellules exprimant la protéinase 3 participant ainsi au maintient de l'inflammation. Ce microenvironnement induit par les macrophages modifie le rôle immuno-modulateur de la clairance des cellules apoptotiques, influençant notamment l'interaction des cellules T naïves avec les cellules dendritiques plasmacytoïdes. La polarisation T résultante présente une distribution déséquilibrée vers les lymphocytes Th2/Th9 et une diminution de la génération de lymphocytes T régulateurs. La protéinase 3, qui est encodée par un gène de réponse au G-CSF, est de plus capable d'induire le recrutement de cellules sur-exprimant cette protéase capable à son tour de stimuler la sécrétion de G-CSF. La protéinase 3 apparait donc, par sa capacité à corrompre les mécanismes de résolution de l'inflammation et d'amplifier sa propre expression dans les cellules recrutées sur le site inflammatoire, comme un élément clé de la physiopathologie de la granulomatose avec polyangéite.
4
Haddad, Yacine. "Rôle de Clec9a dans l'athérosclérose." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB099/document.
Full textAbstract:
L’athérosclérose est une maladie inflammatoire chronique. L’une des caractéristiques des lésions d’athérosclérose est l’accumulation anormale de corps apoptotiques et nécrotiques, due à un défaut d’efferocytose, ceci entraînant la formation du cœur nécrotique. L’évolution de ce cœur nécrotique est également associée à une augmentation de l’inflammation et de la taille des plaques d’athérosclérose, mais aussi dans la survenue de complications telle que la rupture de plaque. Clec9a est un récepteur transmembranaire de type lectine C, majoritairement exprimé par une sous population de cellules dendritiques les DC-CD8α+. Il est capable de reconnaître un ligand spécifiquement exprimé par les corps nécrotiques, l’actine F. L’objectif de notre travail a été de savoir si Clec9a, qui est capable de reconnaître les corps nécrotiques, pouvait être impliqué dans la modulation de l’inflammation observée au cours du développement de l’athérosclérose. Au cours de cette étude, nous avons montré, in vivo partir de deux modèles murins (ApoE-/- et LDLr-/-), que la délétion de Clec9a entraîne une diminution significative de la taille des lésions dans un contexte d’hypercholestérolémie modérée. Cette athéro-protection observée en l’absence de Clec9a, est associée à une augmentation de l’expression de l’IL-10, qui est une interleukine anti-athérogène et anti-inflammatoire. Cet effet athéroprotecteur de l’absence de Clec9a n’est plus observé lorsque l’IL-10 est totalement invalidée. De plus, nous avons montré que l’invalidation de Clec9a spécifiquement dans les DC-CD8α+ entraîne, in vivo, une diminution de l’infiltration des macrophages et des lymphocytes T dans les lésions, ainsi qu’une augmentation de l’expression de l’IL-10, favorisant une diminution de la taille des lésions. La compréhension des mécanismes inflammatoires dans l’athérosclérose constitue un enjeu majeur pour prévenir les risques de complications comme la rupture de plaque ou la thrombose. Ainsi, ce travail met en évidence un nouveau rôle de Clec9a dans la régulation de l’inflammation dans l’athérosclérose et pourrait donc représenter une cible thérapeutique potentielleAtherosclerosis is a chronic inflammatory disease. One of the characteristics of atherosclerotic lesions is the abnormal accumulation of apoptotic and necrotic cells, due to a deficiency of efferocytosis, which leads to the formation of the necrotic heart. The evolution of this necrotic core is also associated with an increase in inflammation and lesions of atherosclerosis, but also in the occurrence of complications such as plaque rupture. Clec9a is a C type lectin receptor, mainly expressed by a subpopulation of dendritic cells, which are the CD8α+ dendritic cells. This receptor is able to recognize a ligand expressed by necrotic cells, the actin F. The aim of our work was to find out if Clec9a, which can sense necrotic cells, could be involved in modulating the inflammation observed during the development of atherosclerosis. In this study, we have shown, in vivo with two mouse models (ApoE - / - and LDLr - / -), that the deletion of Clec9a leads to a significant decrease in the incidence of moderate hypercholesterolemia. This athero-protection observed in the absence of Clec9a, is associated with an increase in the expression of IL-10, which is an anti-atherogenic and anti-inflammatory cytokine. This athero-protective effect of the absence of Clec9a is abolished after total invalidation of IL-10. Furthermore, we report that specific knockdown of Clec9a in CD8α+-DC, in vivo, leads to a decrease in macrophage and lymphocyte infiltration in lesions, as well as an increase in IL-1 expression. 10, which promotes a decrease in lesions size. Understanding of inflammatory mechanisms in atherosclerosis is a major challenge to prevent the risk of complications such as plaque rupture or thrombosis. Thus, this work highlights a new role of Clec9a in the regulation of inflammation in atherosclerosis and could be therefore a potential therapeutic target
5
Pinto, Cristina. "Rôle des cellules myéloïdes et lymphoïdes dans le remodelage cardiaque post-ischémique." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB069.
Full textAbstract:
Après un infarctus, les acteurs de l’immunité innée et adaptative contrôlent le remodelage et la fonction cardiaque. Dans un premier travail, nous nous sommes intéressés aux mécanismes moléculaires définissant le rôle des monocytes et des macrophages, composants majeurs de l’immunité innée. En particulier, nous avons analysé le rôle de deux récepteurs MertK (myeloid-epithelial-reproductive receptor tyrosine kinase) et Mfge8 (milk fat globule epidermal growth factor-like factor 8), susceptibles d’être impliqués dans la reconnaissance des débris cellulaires peuplant la zone infarcie. L’invalidation de MertK et Mfge8 in vivo chez la souris augmente l’accumulation des cellules apoptotiques, aggrave la fibrose et accroit la taille de l’infarctus par rapport aux souris contrôles. De plus, l’expression du facteur pro-angiogenique VEGF-A, est significativement réduite 3 jours post-infarctus chez les souris chimères Mertk-/-Mfge8-/- par rapport aux animaux contrôles. Enfin, l’invalidation de l’expression de VEGF-A dans les cellules myéloides augmente la fibrose et la taille de l’infarctus et diminue la fonction cardiaque. Ainsi, la reconnaissance des débris cellulaires par Mertk et Mfge8 promeut la libération de VEGF-A par les monocytes et macrophages et participe à la restauration de la densité capillaire et de la fonction cardiaque post-infarctus. Dans un deuxième travail, nous avons abordé les voies de signalisation intracellulaires sous-tendant les effets d’un acteur majeur de l’immunité adaptative, le lymphocyte B. Après un infarctus, les lymphocytes B libèrent la chimiokine Ccl7, qui en se fixant sur son récepteur CCR2, déclenche une mobilisation des monocytes inflammatoires de la moelle osseuse vers le sang puis leur recrutement délétère dans la zone infarcie. Nous avons notamment montré que des activateurs des lymphocytes B, comme des stimuli inflammatoires, stimulent la libération de Ccl7, en partie en initiant des voies de signalisation intracellulaires dépendantes du micro-RNA (miR)21. L’administration exogène de lymphocytes B déficients pour miR-21 améliore d’ailleurs la fonction et le remodelage cardiaque post-infarctus chez des souris immunodéficientes. miR21 cible le gène suppresseur de tumeur PTEN et ainsi augmente l’expression du facteur de transcription HIF1α. De fait, l’analyse par échocardiographie effectuée 14 jours après l’induction de l’infarctus montre une amélioration de la fonction cardiaque ainsi qu’une diminution de la taille de l’infarctus et de la fibrose interstitielle chez les souris invalidées pour HIF1α spécifiquement dans les lymphocytes B par rapport aux contrôles. Les taux de la chimiokine CCL7 dans le plasma de ces souris sont aussi significativement réduits à J1 et J3 post infarctus ; ainsi que la mobilisation et le recrutement monocytaire. Il apparaît donc que la voie de signalisation impliquant miR21/HIF1α conditionne l’effet délétère des lymphocytes B dans un contexte d’infarctus aigu du myocarde. Ces travaux ont permis de révéler des facteurs majeurs de la régulation fine de la réaction inflammatoire post-ischémique, et de souligner l’efficacité potentielle de stratégies thérapeutiques modulant l’activité des cellules immunitaires dans le décours des pathologies cardiaquesAfter a myocardial infarction, the innate and adaptive immunity play a role in post ischaemic remodelling and cardiac function. In a first work, we have been interested in the molecular mechanism of the role of monocytes and macrophages, the major innate immunity components. In particular, it has been analysed the function of, the myeloid-epithelial reproductive protein tyrosine kinase (Mertk) and the milk fat globule epidermal growth factor (Mfge8) and their implication in directing cardiac remodelling by skewing the inflammatory response after myocardial infarction. Compared with wild-type, Mertk-deficient (Mertk−/−), or Mfge8- deficient (Mfge8−/−) animals, Mertk−/−/Mfge8−/− mice displayed greater alteration in cardiac function and remodelling. In parallel, Mertk−/−/Mfge8−/− bone marrow chimeras manifested increased accumulation of apoptotic cells, enhanced fibrotic area, and larger infarct size, as well as reduced angiogenesis and VEFA expression. Combined Mertk and Mfge8 deficiency in myeloid cells either obtained from in vitro differentiation of bone marrow cells or isolated from infarcted hearts altered their capacity of efferocytosis and subsequently blunted vascular endothelial growth factor A (VEGFA) release. On the contrary, the recognition of necrotic cells by Mertk and Mfge8 promote VEGFA liberation improving cardiac function and angiogenesis. In the second work, we have focused on intracellular signalling pathway underlying the effects of another important actor of adaptive immunity, the B lymphocytes. After acute myocardial infarction multiple subtypes of inflammatory cells are known to orchestrate post-ischemic cardiac remodelling. In particular, Mature B lymphocytes selectively produce Ccl7 chimiokine and fixed on its CCR2 receptor it is able to induce monocyte mobilization and recruitment to the heart, leading to enhanced tissue injury and deterioration of myocardial function. Many B lymphocytes activators, such as inflammatory stimuli, may promote CCL7 release partially involving an intracellular signalling pathway depending on the micro-RNA miR21. We speculate that endogenous activation of the miR21/HIFα-related pathways balances the effect of B lymphocytes on post-ischemic cardiac remodelling. The treatment with TLR ligands resulted in induction of the microRNA miR-21, which targeted PTEN, leading to subsequent up regulation of HIF1α and HIF2α levels. In Rag1-/- immunodeficient mice with acute MI, we showed that re-supplementation with miR21-/- B lymphocytes restored cardiac repair and function when compared to injection of wild-type B cells. These effects were associated with a reduction in Ly6Chigh monocyte infiltration in the ischemic myocardium as well as with a decrease in infarct size and interstitial fibrosis. This work reveals several factors implicated in regulation of post-ischaemic inflammatory reaction, and underline the potential efficacity of a therapeutic strategy to module the activity of immune cells alongside the cardiovascular diseases
6
Depaire, Agathe. "Altérations de l’efferocytose des macrophages induits par les cellules endothéliales : analyse des mécanismes et approche thérapeutique pour corriger la vasculopathie et la fibrose au cours de la sclérodermie systémique." Electronic Thesis or Diss., Bordeaux, 2024. http://www.theses.fr/2024BORD0481.
Full textAbstract:
La sclérodermie systémique (ScS) est une maladie auto-immune fibrotique chronique incurable. Le concept de réparation tissulaire non résolue, menant à une fibrose persistante, a émergé sur la base d'une inflammation stérile chronique qui transforme une réponse de réparation contrôlée en fibrose pathologique. La résolution efficace de l'inflammation repose notamment sur l’élimination des cellules apoptotiques par les macrophages (Mϕ) via l’efferocytose. Récemment, mon équipe a montré le rôle de la stimulation des cellules endothéliales microvasculaires (CEMV) cutanées par l’IL-1β dans la modulation de la polarisation macrophagique vers un profil mixte M1/M2 inflammatoire, et son implication dans la fibrose cutanée sclérodermique. Une analyse transcriptomique à partir de biopsies cutanées, a mis en évidence une signature de gènes associés à l’efferocytose diminuée chez les patients ScS par rapport aux contrôles. Ce travail visait, par des analyses in vitro à partir de cellules purifiées de la peau de patients ScS ou de sujets sains, à déterminer si les CEMV et l'IL-1β contribuent à l'altération de l’efferocytose au cours de la ScS, et à évaluer les conséquences sur l'activation des fibroblastes et la transition endothélio-mésenchymateuse (EndoMT). Pour cela, les macrophages dérivés de monocytes ont été générés en présence de surnageant de CEMV activées (CEMVIL-1β-Mϕ) ou non (CEMV-Mϕ) par l’IL-1β.Nos résultats mettent en évidence une diminution significative de la phagocytose de Jurkat apoptotiques (apoJK) par les CEMVIL-1β-Mϕ associée à une diminution de l’expression de certains récepteurs directs ou indirects impliqués dans l’efferocytose. D’autre part, l'ajout d'IL-1β pendant la différenciation des MDM0 (contrôle positif de phagocytose) n'a pas altéré leur profil efferocytique global suggérant que l'effet inhibiteur de l'IL-1β ne se manifeste qu'en présence du sécrétome endothélial. Nous avons ensuite étudié les effets du sécrétome macrophagique post-efferocytose sur l’activation fibroblastique et l’EndoMT. Les CEMVIL-1β-Mϕ favorisent le phénotype pro-remodelant et inflammatoire des fibroblastes, effet qui n’est pas limité par la présence de TGF-β et qui est d’autant plus prononcé dans les conditions efferocytiques sclérodermiques. Sur le plan de l’EndoMT nos résultats indiquent que les CEMVIL-1β-Mϕ semblent initier l’EndoMT uniquement dans les conditions ScS en augmentant l’expression de l’α-SMA et de la fibronectine des CEMV. En revanche, les CEMV-Mϕ ont favorisé un phénotype profibrotique des fibroblastes uniquement en présence du surnageant efferocytique combiné au TGF-β et n’induisent pas d’initiation de l’EndoMT.Dans le cadre de cette thèse CIFRE, nous avons exploré le potentiel anti-inflammatoire et pro-résolutif du Résolvix©, candidat médicament développé par la société MIP, basé sur un sécrétome de Mϕ de sujets sains ayant réalisé une efferocytose. Nos résultats montrent qu’en présence de Résolvix©, les fibroblastes sclérodermiques des patients voient diminuer leur profil fibrotique au profit d’un profil remodelant et sécréteur de CCL2. Ce dernier permet également de reverser un profil myofibroblastique déjà établi, tout en favorisant la production de CCL2. Nos données montrent que l’efferocytose joue un rôle variable selon l’état d’activation des CEMV, reflétant potentiellement un rôle séquentiel dans la ScS dans la mesure où l'IL-1β est augmenté dans la peau des patients à des stades précoces, alors que le TGF-β semblent jouer un rôle à des stades tardifs.Ces résultats suggèrent que la restauration d’une efferocytose efficace pourrait limiter l’inflammation et la fibrose au cours de la ScS. Le Résolvix©, pourrait restaurer un environnement tissulaire limitant la fibrose tout en favorisant le recrutement de nouveaux macrophages aux capacités d’efferocytose restaurés chez les patients sclérodermiques ayant des formes tardives avec une fibrose bien établieSystemic sclerosis (SSc) is an incurable chronic fibrotic autoimmune disease. The concept of unresolved tissue repair, leading to persistent fibrosis, has emerged based on chronic sterile inflammation, which transforms a controlled repair response into pathological fibrosis. Effective inflammation resolution relies on macrophages' (Mϕ) efferocytosis, the clearance of apoptotic cells. Recently, my team demonstrated the role of IL-1β-stimulated cutaneous microvascular endothelial cells (MVEC) in modulating macrophage polarization towards a mixed M1/M2 inflammatory profile, implicating this process in cutaneous sclerodermic fibrosis. Transcriptomic analysis from skin biopsies highlighted a gene signature associated with reduced efferocytosis in SSc patients compared to controls. This study aimed, through in vitro analyses of purified cells from SSc patients' or healthy donors' skin, to determine whether MVEC and IL-1β contribute to efferocytosis alteration during SSc and evaluate the consequences on fibroblast activation and endothelial-mesenchymal transition (EndoMT). Monocyte-derived macrophages were generated in the presence of supernatant from MVEC either activated (MVECIL-1β-Mϕ) or not (MVEC-Mϕ) by IL-1β.Our results show a significant reduction in the phagocytosis of apoptotic Jurkat cells (apoJK) by MVECIL-1β-Mϕ, associated with decreased expression of certain direct or indirect receptors involved in efferocytosis. Conversely, adding IL-1β during MDM0 (positive control for phagocytosis) differentiation did not alter their overall efferocytic profile, suggesting that IL-1β's inhibitory effect manifests only in the presence of the endothelial secretome. We then studied the effects of post-efferocytosis macrophage secretome on fibroblast activation and EndoMT. MVECIL-1β-Mϕ promoted a pro-remodeling and inflammatory fibroblast phenotype, unaffected by TGF-β, and more pronounced in sclerodermic efferocytic conditions. Regarding EndoMT, our results indicate that MVECIL-1β-Mϕ appears to initiate EndoMT only in SSc conditions, increasing α-SMA and fibronectin expression in MVEC. However, MVEC-Mϕ promoted a pro-fibrotic fibroblast phenotype only in the presence of efferocytic supernatant combined with TGF-β and did not induce EMT initiation.As part of this CIFRE thesis, we explored the anti-inflammatory and pro-resolutive potential of Résolvix, a drug candidate developed by MIP, based on the secretome of Mϕ from healthy subjects who had undergone efferocytosis. Our results show that in the presence of Résolvix©, sclerodermic fibroblasts from patients exhibit a decrease in their fibrotic profile in favor of a remodeling and CCL2-secreting profile. This also allows for the reversal of an already established myofibroblastic profile while promoting CCL2 production. Our data indicate that efferocytosis plays a variable role depending on the activation state of the vascular endothelial cells, potentially reflecting a sequential role in systemic sclerosis, as IL-1β is elevated in the skin of patients at early stages, while TGF-β seems to play a role at later stages.These results suggest that restoring effective efferocytosis could limit inflammation and fibrosis during SSc. Résolvix© could restore a tissue environment that limits fibrosis while promoting the recruitment of new macrophages with restored efferocytosis capabilities in sclerodermic patients with late-stage forms and established fibrosis
7
Guillet, Stéphanie. "Monogenic predisposition to systemic lupus erythematosus and efferocytosis Impaired efferocytosis and Systemic Lupus Erythematosus in patients with autosomal recessive ACK1 and BRK Kinases deficiencies." Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB003.
Full textAbstract:
Le Lupus Erythemateux disséminé (LED) est un ensemble de maladies auto-immunes caractérisées par la présence d'anticorps anti-nucléaires. La pathogenèse du lupus est inconnue à ce jour et les mécanismes de la maladie pourraient être multiples. Dans ce travail nous reportons l'identification de variants autosomaux récessifs, pertes de function, dans le domaine kinase de ACK1 et BRK respectivement, chez des patients atteints de LED de 2 familles non apparentées. Utilisant des macrophages dérivés d'iPSCs similaires aux macrophages résidents exprimant TIM4, nous montrons que la forme sauvage de ACK1 et BRK n'est pas requise pour la phagocytose de bactéries et de champignons, mais est nécessaire pour une efferocytose efficace, incluant la phagocytose mediée par l'actin de cellules apoptotiques par des macrophages humains et l'expression précoce de gène anti-inflammatoire induit par STAT3 et AKT et déclenché par l'exposition à des cellules apoptotiques. Ces résultats indiquent que l'activité kinase de ACK1 et BRK sont nécessaires pour la clearance immunologiquement silencieuse des cellules apoptotiques par les macrophages. Enfin ces données définissent un sous-groupe de patients atteints de LED avec un déficit génétique d'efferocytose qui pourrait bénéficier de thérapie ciblée dans le futureSystemic Lupus Erythematosus (SLE) is a collection of autoimmune diseases characterized by auto-antibodies against nuclear antigens. Pathogenesis of SLE remains unclear and disease mechanisms may be multiple. Here we report the identification of autosomal recessive loss-of-function variants in the kinase domain of ACK1 and BRK, in patients from two families with SLE. Using patients and controls iPSC-derived Tim4+ resident-like macrophages we find that wild-type ACK1 and BRK are dispensable for phagocytosis of bacteria and fungi, but are both required for efficient efferocytosis, including actin-mediated engulfment of apoptotic cells by human macrophages, and an early cell-autonomous anti-inflammatory gene expression program driven by AKT and STAT3 and triggered by apoptotic cells. These results indicate that ACK1 and BRK kinases activity are required for the immunologically silent clearance of apoptotic cells by macrophages and define genetic efferocytosis deficiency in a subset of SLE patients who may benefit from personalized therapy in the future
8
Lescoat, Alain. "Polarisation macrophagique au cours de la sclérodermie systémique : liens avec les mécanismes d'autoimmunité induite par la silice cristalline et perspectives thérapeutiques dans des modèles in vitro et in vivo." Thesis, Rennes 1, 2020. http://www.theses.fr/2020REN1B026.
Full textAbstract:
La sclérodermie systémique est une maladie auto-immune caractérisée par l’existence d’une vasculopathie chronique et la présence de phénomènes inflammatoires et fibrosants touchant notamment la peau et le poumon. De par leur capacité à adopter un profil de polarisation à la fois pro-inflammatoire et pro-fibrosant, les macrophages pourraient occuper une place importante dans la physiopathologie de la sclérodermie. Cette polarisation macrophagique est conditionnée par les signaux et cytokines présents dans le milieu et qui dépendent notamment des voies de signalisation JAK/STAT. Ce travail démontre que les inhibiteurs de JAK, une classe thérapeutique utilisée dans certaines pathologies inflammatoires chroniques, permettent de limiter à la fois la polarisation pro-inflammatoire et pro-fibrosante des macrophages humains in vitro. Le ruxolitinib, inhibiteur de JAK1/2 permet en particulier de prévenir les manifestations pulmonaires et cutanées. La survenue d’une sclérodermie systémique peut être favorisée par une exposition à certains contaminants environnementaux tels que l’inhalation de silice cristalline. L’élimination de cellules apoptotiques, un processus de résolution de l’inflammation appelé efferocytose, est altérée dans les macrophages dérivés de monocytes sanguins circulants au cours de la sclérodermie systémique. Ce travail démontre que la silice cristalline altère les capacités d’efferocytose de macrophages humains in vitro, dans des proportions similaires à celles observées dans les macrophages de patients sclérodermiques. Cet effet est également observé in vivo dans les macrophages alvéolaires de souris exposées par voie transorale à la silice cristalline. In vitro, des inhibiteurs de la voie RhoA/ROCK permettaient de limiter la diminution de l’efferocytose induite par la silice cristallineSystemic sclerosis (also called scleroderma) is an autoimmune disorder characterized by a chronic vasculopathy with inflammatory and pro-fibrotic manifestations in lungs and skin. As they can adopt pro-inflammatory and pro-fibrotic activation states, macrophages could play a key role in the pathogenesis of scleroderma. Macrophage polarization depends on surrounding activating factors such as cytokines that involve pathways including JAK/STAT signaling. This work demonstrates that JAK inhibitors, a new therapeutic class currently in use for the treatment of some inflammatory chronic diseases, can limit pro-inflammatory and pro-fibrotic polarization profile of human macrophages in vitro. Ruxolitinib, a JAK1/2 inhibitor can prevent the cutaneous and pulmonary manifestations of the disease in a mouse model of scleroderma and limits pro-inflammatory and pro-fibrotic activation of macrophages in these tissues.Although it is considered as an idiopathic disorder, the onset of systemic sclerosis can be triggered by exposure to environmental contaminants such as crystalline silica inhalation. A defect of apoptotic cell clearance, a process also called efferocytosis, is noticed in monocyte-derived-macrophages from patients with systemic sclerosis. This work demonstrates that crystalline silica impairs efferocytosis capacities of human macrophages in vitro, similarly to the defect observed in scleroderma patients. The same effect is observed in vivo, in alveolar macrophages from mice exposed to crystalline silica through transoral instillation. In vitro, inhibitors of the RhoA/ROCK pathway can limit the impairment of efferocytosis capacities of macrophages induced by exposure to crystalline silica
9
Hermetet, Francois. "La dualité de l'apoptose des cellules du cancer du col de l'utérus ou la face de Janus de l'apoptose : un objectif thérapeutique et une implication dans le transfert horizontal d'oncogènes viraux." Thesis, Besançon, 2015. http://www.theses.fr/2015BESA3009/document.
Full textAbstract:
À l'heure actuelle, une large proportion des recherches vouées à l'identification et au développement de nouvelles thérapies anticancéreuses est basée sur l'apoptose. Dans les dernières décennies, divers composés phytochimiques ont été caractérisés comme des agents pharmacologiques susceptibles d'éliminer les cellules cancéreuses via l'induction de l'apoptose. Parmi ceux-ci, l'isoliquiritigénine (ILG), un flavonoïde naturellement présent dans les racines de réglisse, se distingue des autres par ses nombreuses propriétés thérapeutiques incluant une activité antitumorale. Chez les mammifères, les cellules apoptotiques (CA) peuvent être complètement dégradées via leur capture par des cellules phagocytaires spécialisées ou servir de vecteurs d'ADN dans un processus appelé transfert horizontal de gènes (THG). Ainsi, il a été mis en évidence que des CA dérivées de cancer du col de l'utérus peuvent induire le transfert de séquences d'oncogènes de papillomavirus humains (HPV) à des fibroblastes primaires humains (HPFs) qui acquièrent des propriétés de cellules transformées. Cependant, les mécanismes cellulaires et moléculaires impliqués dans l'internalisation de CA par les fibroblastes, un modèle de phagocyte non-professionnel, n'ont pas encore été clairement identifiés et la caractérisation de ces événements qui précèdent le THG est essentielle à la compréhension de ce processus et de la transformation des cellules receveuses qui peut en découler.Dans ce contexte, les objectifs de cette thèse étaient, (i) d'analyser les effets anticancéreux de l'ILG sur des cellules dérivées de cancer du col de l'utérus, (ii) de caractériser les mécanismes cellulaires et moléculaires impliqués dans la capture des CA par les HPFs, (iii) d'étudier les événements cellulaires qui font suite à ce processus comme la maturation des phagosomes, le THG et l'acquisition de propriétés de transformation et enfin, (iv) de démontrer la preuve de la conservation de la capacité tumorigénique des CA in vivo.Un premier travail a permis de mettre en lumière les propriétés antitumorales de l'ILG via une multiplicité d'actions sur des modèles cellulaires de cancer du col de l'utérus in vitro, incluant des activités anti-proliférative, pro-apoptotique, anti-migratoire. Concernant la lignée cellulaire Ca Ski, p53 sauvage et représentative du carcinome du col utérin le plus fréquent, associé à une infection transformante par HPV16, l'apoptose induite par l'ILG semble dépendante de p53 et de la mitochondrie, mais aussi de la voie des récepteurs de mort, comme attesté par l'augmentation des niveaux de protéines p53 et p21, la dissipation du potentiel membranaire mitochondrial, la libération du cytochrome c et le clivage des caspases-9, -8 et -3. Ces effets pourraient être la conséquence de la diminution de l'expression de l'oncoprotéine virale E6 d'HPV16 induite par l'ILG entraînant la restauration de l'expression de p53. Nos travaux révèlent un fort potentiel de l'ILG contre différents types de cellules malignes et ouvrent le champ à de nouvelles modalités de traitement des cancers associés à HPVMost of the research strategies aiming at improving anticancer therapies currently target apoptosis. Over the last decades, several natural products derived from herbal medicine or food have been identified as pharmacological agents for cancer cell elimination through apoptosis induction. Among them, isoliquiritigenin (ILG) is a chalcone derivative isolated from liquorice and shallots which exhibits a wide variety of biological functions including antitumor properties.In mammals, apoptotic cells (AC) can either be eliminated after their capture by specialized phagocytes or act as vectors of DNA in a process named horizontal gene transfer (HGT). For instance, AC derived from cervical cancer cells can transfer human papillomavirus (HPV) oncogene sequences to human primary fibroblasts (HPFs) which subsequently acquire transformed cell properties. The molecular mechanisms underlying AC uptake by HPFs, a model of non-professional phagocytes, have not been clearly identified. Characterizing these upstream events appears critical to broaden our understanding of HGT and the ultimate transformation of recipient cells which may subsequently occur.The aims of this work were to (i) study the antitumor effects of ILG on cervical cancer cell lines,(ii) characterize the cellular and molecular mechanisms underlying AC uptake by HPF, (iii) study the cellular events which occur in HPFs following AC engulfment such as phagosome maturation, HGT and acquisition of transformed properties, and (iv) evaluate the tumorigenic properties of AC in vivo.In a first part of this PhD project, we found that ILG exhibits multiple antitumor actions on cervical cancer cells in vitro including anti-proliferative, pro-apoptotic and anti-migration properties. Further studies on apoptosis-related events were conducted in Ca Ski cells (p53wt, HPV16 DNA positive), which are representative of the most frequent cervical carcinoma. The treatment of Ca Ski cells with ILG is associated with increased levels of p53 and p21 proteins, loss of mitochondrial membrane potential, cytochrome c release and caspase-9, -8 and -3 cleavage. These features suggest that ILG-induced apoptosis is dependent on p53 and involve both mitochondrial and death receptor- mediated pathways. The effect of ILG in Ca Ski cells may be partly explained by the decrease of HPV16 E6 oncoprotein expression and the associated raise of p53 levels observed after cell treatment. Our work highlights the potential of ILG as an antitumor agent and provides the opportunity of new treatment. ln the second part of this work, we set up a method based on flow cytometry to quantitatively analyze AC uptake. This original method and microscopy analysis allowed us to show that HPFs act as non-professional phagocytes and are able to engulf subcellular fragments rather than dying whole cells, with lower efficiency and rapidity compared to professional phagocytes as macrophages. Uptake of AC by HPFs depends on time, temperature and the presence of bivalent ions. Morphological analysis and fonctional assays using endocytosis inhibitors revealed a mechanism related to phagocytosis and/or macropinocytosis. The recognition of phosphatidylserine exposed on the surface of AC by their receptor BAIl has emerged as a required event for AC uptake by HPFs
10
Martin, Constance Jean. "Efferocytosis is an Innate Antibacterial Mechanism of Mycobacterium tuberculosis Control." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10094.
Full textAbstract:
One third of the world’s population is infected with Mycobacterium tuberculosis, causing two million deaths annually. The bacteria avoid immune clearance by persisting within macrophages by subverting normal phagosome maturation and acidification. In order to spread, the bacteria induce necrotic death of its host macrophage, broadcasting the infection into neighboring cells. However, it has long been appreciated that the apoptotic, rather than necrotic death of an infected macrophage results in bacterial growth suppression, improved adaptive immune response and survival. The mechanism for apoptosis-mediated bacterial suppression has hitherto remained unknown. In this dissertation we report that apoptosis itself is not intrinsically bactericidal. We find that following apoptosis, the M. tuberculosis-infected macrophage is engulfed by bystander macrophages through the process of efferocytosis. Efferocytosis, or apoptotic cell clearance, is a critical function of macrophages; however, little is known regarding efferocytosis of infected apoptotic cells. We find that M. tuberculosis-infected macrophages die by apoptosis more commonly than found previously. By confocal microscopy we observed that apoptotic macrophages are rapidly engulfed by uninfected macrophages. Efferocytosis of M. tuberculosisinfected macrophages occurs in vitro with all macrophage types tested and in vivo- specifically in the lung, indicating that efferocytosis could play an important role during infection. We developed an uninfected macrophage co-culture system in which we observe efferocytosis and define conditions in which it occurs. Using this co-culture system we observe a suppression of bacterial growth. By blocking efferocytosis, we have found that the engulfment of infected cells is required for M. tuberculosis control in the macrophage co-culture system, demonstrating that efferocytosis is a novel antibacterial mechanism. We then demonstrated using transmission electron microscopy that the M. tuberculosis-containing efferocytic phagosome is structurally distinct from the traditional M. tuberculosis phagosome. Bacteria from within the efferocytic phagosome are unable to halt its maturation, and as such are delivered to lysosomes. Furthermore, we find that following efferocytosis, M. tuberculosis are killed. While efferocytosis is recognized as a constitutive housekeeping function of macrophages, our work indicates that is should also be viewed as an antimicrobial effector mechanism.
Book chapters on the topic "Efferocytose"
1
Brix, Nikko, Anna Tiefenthaller, and Kirsten Lauber. "Efferocytosis." In Encyclopedia of Cancer, 1–7. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-642-27841-9_7215-1.
Full text
2
Brix, Nikko, Anna Tiefenthaller, and Kirsten Lauber. "Efferocytosis." In Encyclopedia of Cancer, 1475–81. Berlin, Heidelberg: Springer Berlin Heidelberg, 2015. http://dx.doi.org/10.1007/978-3-662-46875-3_7215.
Full text
3
Evans, Amanda L., Jack W. D. Blackburn, Charles Yin, and Bryan Heit. "Quantitative Efferocytosis Assays." In Methods in Molecular Biology, 25–41. New York, NY: Springer New York, 2016. http://dx.doi.org/10.1007/978-1-4939-6581-6_3.
Full text
4
Taefehshokr, Nima, and Bryan Heit. "Methods for Quantitative Efferocytosis Assays." In Methods in Molecular Biology, 41–59. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-3338-0_4.
Full text
5
Gage, Matthew C. "Measuring Apoptotic Cell Engulfment (Efferocytosis) Efficiency." In Methods in Molecular Biology, 143–52. New York, NY: Springer New York, 2019. http://dx.doi.org/10.1007/978-1-4939-9130-3_11.
Full text
6
Martinez, Jennifer. "Prix Fixe: Efferocytosis as a Four-Course Meal." In Current Topics in Microbiology and Immunology, 1–36. Cham: Springer International Publishing, 2015. http://dx.doi.org/10.1007/82_2015_467.
Full text
7
Gachanja, Naomi N., David A. Dorward, Adriano G. Rossi, and Christopher D. Lucas. "Assays of Eosinophil Apoptosis and Phagocytic Uptake." In Methods in Molecular Biology, 113–32. New York, NY: Springer US, 2021. http://dx.doi.org/10.1007/978-1-0716-1095-4_10.
Full textAbstract:
AbstractEosinophil apoptosis (programmed cell death) plays an important role in several inflammatory and allergic conditions. Apoptosis triggers various mechanisms including activation of cysteine-aspartic proteases (caspases) and is characterized by morphological and biochemical changes. These include cellular condensation, nuclear fragmentation, increased mitochondrial permeability with loss of membrane potential, and exposure of phosphatidylserine on the cell membrane. A greater understanding of apoptotic mechanisms, subsequent phagocytosis (efferocytosis), and regulation of these processes is critical to understanding disease pathogenesis and development of potential novel therapeutic agents. Release of soluble factors and alterations to surface marker expression by eosinophils undergoing apoptosis aid them in signaling their presence to the immediate environment, and their subsequent recognition by phagocytic cells such as macrophages. Uptake of apoptotic cells usually suppresses inflammation by restricting proinflammatory responses and promoting anti-inflammatory and tissue repair responses. This, in turn, promotes resolution of inflammation. Defects in the apoptotic or efferocytosis mechanisms perpetuate inflammation, resulting in chronic inflammation and enhanced disease severity. This can be due to increased eosinophil life span or cell necrosis characterized by loss of cell membrane integrity and release of toxic intracellular mediators. In this chapter, we detail some of the key assays that are used to assess eosinophil apoptosis, as well as the intracellular signaling pathways involved and phagocytic clearance of these cells.
8
Aranda-Pardos, Irene, Achmet Imam-Chasan, and Noelia Alonso-Gonzalez. "Studying Efferocytosis Dynamics in Tissue-Resident Macrophages Ex Vivo." In Methods in Molecular Biology, 389–405. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-3437-0_27.
Full text
9
Werfel, Thomas A. "Assessment of the Immune Response to Tumor Cell Apoptosis and Efferocytosis." In Methods in Molecular Biology, 45–55. New York, NY: Springer US, 2022. http://dx.doi.org/10.1007/978-1-0716-2553-8_5.
Full text
10
Dickson, Brandon H., and Bryan Heit. "Analysis of Efferocytic Receptor Dynamics and Synapse Formation in a Frustrated Efferocytosis Model." In Methods in Molecular Biology, 61–77. New York, NY: Springer US, 2023. http://dx.doi.org/10.1007/978-1-0716-3338-0_5.
Full textConference papers on the topic "Efferocytose"
1
Liu, G., Y. Park, and E. Abraham. "Urokinase Receptor Regulates Neutrophil Efferocytosis." In American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California. American Thoracic Society, 2009. http://dx.doi.org/10.1164/ajrccm-conference.2009.179.1_meetingabstracts.a1358.
Full text
2
Desch, Ashley N., Gwendalyn J. Randolph, Robert J. Mason, Peter M. Henson, and Claudia Jakubzick. "Pulmonary Dendritic Cell Specificity Of Efferocytosis." In American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado. American Thoracic Society, 2011. http://dx.doi.org/10.1164/ajrccm-conference.2011.183.1_meetingabstracts.a2838.
Full text
3
Fernandez-Boyanapalli, Ruby, Christena A. Kolakowski, Donna L. Bratton, and E. R. Sutherland. "Obesity Impairs Efferocytosis In The Asthmatic Airway." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a5610.
Full text
4
Petrusca, Daniela N., Matthew J. Justice, Robert Bittman, Kelly Schweitzer, Walter C. Hubbard, Homer L. Twigg, and Irina Petrache. "FTY720 Analogs Improve Alveolar Macrophages Efferocytosis During Cigarette Smoking." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5551.
Full text
5
Ryan, EM, R. Budd, MA Bewley, P. Coelho, W. Rumsey, Y. Sanchez, G. Choudhury, et al. "S115 Mechanisms to reverse impaired macrophage efferocytosis in copd." In British Thoracic Society Winter Meeting 2017, QEII Centre Broad Sanctuary Westminster London SW1P 3EE, 6 to 8 December 2017, Programme and Abstracts. BMJ Publishing Group Ltd and British Thoracic Society, 2017. http://dx.doi.org/10.1136/thoraxjnl-2017-210983.121.
Full text
6
Zhong, Xiancai, Ha-Na Lee, and Young-Joon Surh. "Abstract 825: Myc-nick promotes efferocytosis through M2 macrophage polarization." In Proceedings: AACR 107th Annual Meeting 2016; April 16-20, 2016; New Orleans, LA. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/1538-7445.am2016-825.
Full text
7
McCaslin, Charles A., Daniela Petrusca, Gregory Anderson, and Irina Petrache. "Effects Of Biofilm Forming Pseudomonas Aeruginosa On Alveolar Macrophage Efferocytosis." In American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California. American Thoracic Society, 2012. http://dx.doi.org/10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a5257.
Full text
8
Cook, Rebecca S. "Abstract A126: Taking out the trash: Efferocytosis in the tumor microenvironment." In Abstracts: CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. American Association for Cancer Research, 2016. http://dx.doi.org/10.1158/2326-6074.cricimteatiaacr15-a126.
Full text
9
Petrusca, Daniela N., Jeremy Adamowicz, Natalia I. Rush, Amanda J. Fisher, Matthew J. Justice, Patricia Smith, Yuan Gu, et al. "Ceramide-dependent Modulation Of Apoptotic Cell Clearance (efferocytosis) By Alveolar Macrophages." In American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans. American Thoracic Society, 2010. http://dx.doi.org/10.1164/ajrccm-conference.2010.181.1_meetingabstracts.a1268.
Full text
10
Parekh, Dhruv, Gavin Perkins, and David Thickett. "LSC Abstract – Vitamin D stimulates macrophage efferocytosis and encourages a proresolution phenotype." In ERS International Congress 2016 abstracts. European Respiratory Society, 2016. http://dx.doi.org/10.1183/13993003.congress-2016.pa938.
Full text