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David M Engman - One of the best experts on this subject based on the ideXlab platform.
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enhanced Efferocytosis of apoptotic cardiomyocytes through myeloid epithelial reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction
Circulation Research, 2013Co-Authors: Xin Yi Yeap, Shirley Dehn, Rachael L Terry, Margaret L Novak, Shuang Zhang, Shinichi Iwata, Shunichi Homma, Konstantinos Drosatos, Jon W Lomasney, David M EngmanAbstract:Rationale:Efficient clearance of apoptotic cells (Efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of Efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between Efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective:We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting Efferocytosis during myocardial infarction. Methods and Results:In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for Efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occl...
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enhanced Efferocytosis of apoptotic cardiomyocytes through mer tyrosine kinase links acute inflammation resolution to cardiac repair after infarction
Circulation Research, 2013Co-Authors: Xin Yi Yeap, Shirley Dehn, Rachael L Terry, Margaret L Novak, Shuang Zhang, Shinichi Iwata, Shunichi Homma, Konstantinos Drosatos, Jon W Lomasney, David M EngmanAbstract:Rationale: Efficient clearance of apoptotic cells (Efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of Efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between Efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective: We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting Efferocytosis during MI. Methods and Results: In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for Efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo Efferocytosis. Importantly, suppressed Efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk ; reciprocal transplantation of Mertk +/+ marrow into Mertk -/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI. Conclusions: These data collectively and directly link Efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.
Xin Yi Yeap - One of the best experts on this subject based on the ideXlab platform.
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enhanced Efferocytosis of apoptotic cardiomyocytes through myeloid epithelial reproductive tyrosine kinase links acute inflammation resolution to cardiac repair after infarction
Circulation Research, 2013Co-Authors: Xin Yi Yeap, Shirley Dehn, Rachael L Terry, Margaret L Novak, Shuang Zhang, Shinichi Iwata, Shunichi Homma, Konstantinos Drosatos, Jon W Lomasney, David M EngmanAbstract:Rationale:Efficient clearance of apoptotic cells (Efferocytosis) is a prerequisite for inflammation resolution and tissue repair. After myocardial infarction, phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes. The molecular mechanisms of Efferocytosis of cardiomyocytes and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between Efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective:We set out to identify mechanisms of dying cardiomyocyte engulfment by phagocytes and, for the first time, to assess the causal significance of disrupting Efferocytosis during myocardial infarction. Methods and Results:In contrast to other apoptotic cell receptors, macrophage myeloid-epithelial-reproductive tyrosine kinase was necessary and sufficient for Efferocytosis of cardiomyocytes ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occl...
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enhanced Efferocytosis of apoptotic cardiomyocytes through mer tyrosine kinase links acute inflammation resolution to cardiac repair after infarction
Circulation Research, 2013Co-Authors: Xin Yi Yeap, Shirley Dehn, Rachael L Terry, Margaret L Novak, Shuang Zhang, Shinichi Iwata, Shunichi Homma, Konstantinos Drosatos, Jon W Lomasney, David M EngmanAbstract:Rationale: Efficient clearance of apoptotic cells (Efferocytosis) is a prerequisite for inflammation resolution and tissue repair. Following myocardial infarction (MI), phagocytes are recruited to the heart and promote clearance of dying cardiomyocytes (CMs). The molecular mechanisms of Efferocytosis of CMs and in the myocardium are unknown. The injured heart provides a unique model to examine relationships between Efferocytosis and subsequent inflammation resolution, tissue remodeling, and organ function. Objective: We set out to identify mechanisms of dying cardiomyocyte (CM) engulfment by phagocytes and to for the first time assess the causal significance of disrupting Efferocytosis during MI. Methods and Results: In contrast to other apoptotic cell receptors, macrophage MER tyrosine kinase (MER-TK) was necessary and sufficient for Efferocytosis of CMs ex vivo. In mice, Mertk was specifically induced in Ly6cLO myocardial phagocytes after experimental coronary occlusion. Mertk deficiency led to an accumulation of apoptotic CMs, independent of changes in non-CMs, and a reduced index of in vivo Efferocytosis. Importantly, suppressed Efferocytosis preceded increases in myocardial infarct size and led to delayed inflammation resolution and reduced systolic performance. Reduced cardiac function was reproduced in chimeric mice deficient in bone marrow Mertk ; reciprocal transplantation of Mertk +/+ marrow into Mertk -/- mice corrected systolic dysfunction. Interestingly, an inactivated form of MERTK, known as solMER, was identified in infarcted myocardium, implicating a natural mechanism of MERTK inactivation post MI. Conclusions: These data collectively and directly link Efferocytosis to wound healing in the heart and identify Mertk as a significant link between acute inflammation resolution and organ function.
Jodie L. Simpson - One of the best experts on this subject based on the ideXlab platform.
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Galectin-3 enhances monocyte-derived macrophage Efferocytosis of apoptotic granulocytes in asthma
Respiratory Research, 2019Co-Authors: Melanie Erriah, Kavita Pabreja, Michael Fricker, Katherine J. Baines, Louise E. Donnelly, Johan Bylund, Anna Karlsson, Jodie L. SimpsonAbstract:Background Galectin-3 is a 32 kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (Efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired Efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes. Methods Eligible non-smoking adults with asthma ( n = 19), including 7 with NEA and healthy controls ( n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and Efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array. Results Baseline Efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved Efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = − 0.671; p = 0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p = 0.044) while IL-6 and CXCL8 levels were similar. Conclusions Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired Efferocytosis in NEA.
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galectin 3 enhances monocyte derived macrophage Efferocytosis of apoptotic granulocytes in asthma
Respiratory Research, 2019Co-Authors: Melanie Erriah, Kavita Pabreja, Michael Fricker, Katherine J. Baines, Louise E. Donnelly, Johan Bylund, Anna Karlsson, Jodie L. SimpsonAbstract:Galectin-3 is a 32 kDa protein secreted by macrophages involved in processes such as cell activation, chemotaxis and phagocytosis. Galectin-3 has previously been shown to improve the ability of airway macrophages to ingest apoptotic cells (Efferocytosis) in chronic obstructive pulmonary disease (COPD) and may be of interest in non-eosinophilic asthma (NEA) which is also characterised by impaired Efferocytosis. It was hypothesised that the addition of exogenous galectin-3 to monocyte-derived macrophages (MDMs) derived from donors with NEA would enhance their ability to engulf apoptotic granulocytes. Eligible non-smoking adults with asthma (n = 19), including 7 with NEA and healthy controls (n = 10) underwent a clinical assessment, venepuncture and sputum induction. MDMs were co-cultured with apoptotic granulocytes isolated from healthy donors with or without exogenous recombinant galectin-3 (50 μg/mL) and Efferocytosis was assessed by flow cytometry. Galectin-3 expression and localisation in MDMs was visualised by immunofluorescence staining and fluorescence microscopy. Galectin-3, interleukin (IL)-6 and CXCL8 secretion were measured in cell culture supernatants by ELISA and cytometric bead array. Baseline Efferocytosis (mean (±standard deviation)) was lower in participants with asthma (33.2 (±17.7)%) compared with healthy controls (45.3 (±15.9)%; p = 0.081). Efferocytosis did not differ between the participants with eosinophilic asthma (EA) (31.4 (±19.2)%) and NEA (28.7 (±21.5)%; p = 0.748). Addition of galectin-3 significantly improved Efferocytosis in asthma, particularly in NEA (37.8 (±18.1)%) compared with baseline (30.4 (±19.7)%; p = 0.012). Efferocytosis was not associated with any of the clinical outcomes but was negatively correlated with sputum macrophage numbers (Spearman r = − 0.671; p = 0.017). Galectin-3 was diffusely distributed in most MDMs but formed punctate structures in 5% of MDMs. MDM galectin-3 secretion was lower in asthma (9.99 (2.67, 15.48) ng/mL) compared with the healthy controls (20.72 (11.28, 27.89) ng/mL; p = 0.044) while IL-6 and CXCL8 levels were similar. Galectin-3 modulates macrophage function in asthma, indicating a potential role for galectin-3 to reverse impaired Efferocytosis in NEA.
Ira Tabas - One of the best experts on this subject based on the ideXlab platform.
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Efferocytosis in health and disease
Nature Reviews Immunology, 2020Co-Authors: Amanda C Doran, Arif Yurdagul, Ira TabasAbstract:The clearance of apoptotic cells by professional and non-professional phagocytes — a process termed ‘Efferocytosis’ — is essential for the maintenance of tissue homeostasis. Accordingly, defective Efferocytosis underlies a growing list of chronic inflammatory diseases. Although much has been learnt about the mechanisms of apoptotic cell recognition and uptake, several key areas remain incompletely understood. This Review focuses on new discoveries related to how phagocytes process the metabolic cargo they receive during apoptotic cell uptake; the links between Efferocytosis and the resolution of inflammation in health and disease; and the roles of Efferocytosis in host defence. Understanding these aspects of Efferocytosis sheds light on key physiological and pathophysiological processes and suggests novel therapeutic strategies for diseases driven by defective Efferocytosis and impaired inflammation resolution. Clearing away dead cells — a process known as Efferocytosis — is crucial for normal tissue homeostasis and is impaired in several pathological processes. This Review describes new insights into how efferocytes deal with the engulfed dead cell cargo, how Efferocytosis supports the resolution of inflammation and how this understanding is informing new therapeutic strategies.
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mechanisms and consequences of defective Efferocytosis in atherosclerosis
Frontiers in Cardiovascular Medicine, 2018Co-Authors: Arif Yurdagul, Amanda C Doran, Gabrielle Fredman, Ira TabasAbstract:Efficient clearance of apoptotic cells, termed Efferocytosis, critically regulates normal homeostasis whereas defective uptake of apoptotic cells results in chronic and non-resolving inflammatory diseases, such as advanced atherosclerosis. Monocyte-derived macrophages recruited into developing atherosclerotic lesions initially display efficient Efferocytosis and temper inflammatory responses, processes that restrict plaque progression. However, during the course of plaque development, macrophages undergo cellular reprogramming that reduces efferocytic capacity, which results in post-apoptotic necrosis of apoptotic cells and inflammation. Furthermore, defective Efferocytosis in advanced atherosclerosis is a major driver of necrotic core formation, which can trigger plaque rupture and acute thrombotic cardiovascular events. In this review, we discuss the molecular and cellular mechanisms that regulate Efferocytosis, how Efferocytosis promotes the resolution of inflammation, and how defective Efferocytosis leads to the formation of clinically dangerous atherosclerotic plaques.
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an axl lrp 1 ranbp9 complex mediates dc Efferocytosis and antigen cross presentation in vivo
Journal of Clinical Investigation, 2014Co-Authors: Manikandan Subramanian, Edward B Thorp, Crystal D Hayes, Joseph J C Thome, Glenn K Matsushima, Joachim Herz, Donna L Farber, Madepalli K Lakshmana, Ira TabasAbstract:The phagocytosis of apoptotic cells (ACs), or Efferocytosis, by DCs is critical for self-tolerance and host defense. Although many Efferocytosis-associated receptors have been described in vitro, the functionality of these receptors in vivo has not been explored in depth. Using a spleen Efferocytosis assay and targeted genetic deletion in mice, we identified a multiprotein complex — composed of the receptor tyrosine kinase AXL, LDL receptor–related protein–1 (LRP-1), and RAN-binding protein 9 (RANBP9) — that mediates DC Efferocytosis and antigen cross-presentation. We found that AXL bound ACs, but required LRP-1 to trigger internalization, in murine CD8α+ DCs and human-derived DCs. AXL and LRP-1 did not interact directly, but relied on RANBP9, which bound both AXL and LRP-1, to form the complex. In a coculture model of antigen presentation, the AXL/LRP-1/RANBP9 complex was used by DCs to cross-present AC-associated antigens to T cells. Furthermore, in a murine model of herpes simplex virus–1 infection, mice lacking DC-specific LRP-1, AXL, or RANBP9 had increased AC accumulation, defective viral antigen-specific CD8+ T cell activation, enhanced viral load, and decreased survival. The discovery of this multiprotein complex that mediates functionally important DC Efferocytosis in vivo may have implications for future studies related to host defense and DC-based vaccines.
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mechanisms and consequences of Efferocytosis in advanced atherosclerosis
Journal of Leukocyte Biology, 2009Co-Authors: Edward B Thorp, Ira TabasAbstract:Throughout atherosclerotic lesion development, intimal macrophages undergo apoptosis, a form of death that usually prevents cellular necrosis. In advanced atherosclerotic lesions, however, these apoptotic macrophages become secondarily necrotic and coalesce over time into a key feature of vulnerable plaques, the necrotic core. This event is critically important, as necrotic core formation in these advanced atheromata is thought to promote plaque disruption and ultimately, acute atherothrombotic vascular disease. Increasing evidence suggests that the mechanism behind postapoptotic macrophage necrosis in advanced atherosclerosis is defective phagocytic clearance or “Efferocytosis” of the apoptotic cells. Thus, understanding the cellular and molecular mechanisms of Efferocytosis in atherosclerosis and why Efferocytosis becomes defective in advanced lesions is an important goal. Molecular–genetic causation studies in mouse models of advanced atherosclerosis have provided evidence that several molecules known to be involved in Efferocytosis, including TG2, MFG-E8, complement C1q, Mertk, lysoPC, and Fas, play important roles in the clearance of apoptotic cells in advanced plaques. These and future insights into the molecular mechanisms of defective Efferocytosis in advanced atheromata may open the way for novel therapeutic strategies for atherothrombotic vascular disease, the leading cause of death in the industrialized world.
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Apoptosis and Efferocytosis in mouse models of atherosclerosis.
Current Drug Targets, 2007Co-Authors: Ira TabasAbstract:Throughout the process of atherosclerosis, lesional macrophages, smooth muscle cells, and possibly endothelial cells undergo programmed cell death, or apoptosis. Under normal physiologic conditions, apoptotic cells are rapidly cleared by neighboring phagocytes, a process called Efferocytosis, which prevents secondary cellular necrosis and inflammation. If Efferocytosis is not efficient, necrosis, inflammation, and tissue damage ensue. Mouse models of atherosclerosis offer the best opportunity to understand the mechanisms and consequences of lesional cell apoptosis and Efferocytosis in atherogenesis and plaque progression. Studies in mice to date have suggested that properly coupled macrophage apoptosis and Efferocytosis in early atherosclerosis limits lesion size. The results of other mouse studies suggest that macrophage and smooth muscle cell apoptosis and defective Efferocytosis in advanced lesions promotes plaque necrosis. Future insight into these critically important processes will require additional insight into the molecular and cellular mechanisms that lead to lesional cell apoptosis and Efferocytosis as well as new mouse models of plaque disruption and thrombosis. Advances in these areas offer great hope for eventual translation into innovative therapeutic strategies to combat atherothrombotic vascular disease.
Rebecca S Cook - One of the best experts on this subject based on the ideXlab platform.
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Efferocytosis in the Tumor Microenvironment
Encyclopedia of Cell Biology, 2020Co-Authors: David B. Vaught, Jamie C. Stanford, Rebecca S CookAbstract:Cell death in response to physiological cues is a feature of many normal tissues, and often occurs due to tissue damage or disease. Regardless of the reason, dying cells require their rapid removal from the tissue in order to maintain homeostasis in the tissue, prevent potential cytotoxic immunity against self-antigens, and to promote wound healing. Phagocytic removal of dying cells is referred to as Efferocytosis, a process necessary for sterile wound healing. Interestingly, malignant tumor progression has long been compared to wound healing, and recent evidence demonstrates a molecular link between Efferocytosis and tumor a ‘wound healing’ phenotype. We discuss the impact of Efferocytosis in the normal breast and in breast cancers.
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Abstract A126: Taking out the trash: Efferocytosis in the tumor microenvironment
Cancer immunology research, 2020Co-Authors: Rebecca S CookAbstract:We have examined the malignant tumor microenvironment (TME) from a perspective that is often noted but overlooked: tissue repair. It has long been observed that tumors resemble ‘wounds that do not heal,’ but the reasons remain obscured. We found that macrophages in the tumor microenvironment orchestrate wound healing and immune tolerance in response to tumor cell death, a feature common to all solid tumors. We used genetic and pharmacological methods to block macrophage-mediated engulfment of dying tumor cells, a process referred to as Efferocytosis. We found that MerTK-mediated Efferocytosis of dying tumor cells induces macrophage-mediated production of Th2-like cytokines, including IL-4, IL-13, IL-10, and TGF-beta. Blockade of the receptor tyrosine kinase MerTK through pharmacological tyrosine kinase inhibition or through genetic MerTK abalation blocked macrophage-mediated Efferocytosis in the tumor microenvironment, impairing M2-like macrophage polarization and expression of Th2-like cytokines in the tumor microenvironment. Because cell death is a major histological feature of the breast during post-partum involution of milk-producing breast epithelia, we studied the impact of MerTK-mediated Efferocytosis in a model of post-partum breast cancer (ppBC). Currently, ppBC accounts for nearly 25% of all breast cancers in young (pre-menopausal) women. In contrast to breast cancers diagnosed during pregnancy, which correlate with a favorable prognosis, ppBCs are highly aggressive, metastatic, and life-threatening, even when corrected for molecular breast cancer subtype and for the age of the woman at diagnosis. We used genetic and pharmacological methods to block MerTK-mediated Efferocytosis in ppBCs, demonstrating that Efferocytosis increased ppBC metastasis by nearly 10-fold, but that genetic or pharmacological MerTK inhibition markedly decreased metastasis in ppBCS. Similarly, targeted inhibition of Efferocytosis-induced cytokines, including TGF-beta, substantially reduced metastasis of Efferocytosis-competent ppBCs. Collagen deposition, TReg expansion, and Th2 cytokine upregulation were found to be dependent on Efferocytosis-induced TGF-beta signaling. These findings in ppBC, in which widespread tumor cell death was initiated by physiological post-partum involution, prompted our interest in the impact of therapeutically-induced cell death and subsequent Efferocytosis on pro-malignant leukocyte behaviors in the tumor microenvironment. As many as 70-80% of primary breast tumors treated with cytotoxic chemotherapy show a partial response in the pre-surgical (neoadjuvant) setting, and lack of a pathological complete response (pCR) is a strong predictor of tumor recurrence following surgical tumor excision. We tested the hypothesis that Efferocytosis, the immune system9s inherent response to cell death, results in tumor repair (increased ‘wound healing’) in response to cytotoxic treatment. In support of this hypothesis, a single dose of doxorubicin or lapatinib induced a transient wave tumor cell death within 24 hours, followed at post-treatment day 4 with increased M2 macrophages and TRegs within the tumor microenvironment, and increased expression of Th2-like cytokines. Importantly, increased metastases were seen in tumor-bearing mice treated once with doxorubicin over what was seen in untreated mice. However, targeted inhibition of Efferocytosis using a MerTK kinase inhibitor (TKIs) in combination with doxorubicin blocked expression of Th2-like cytokines, limited the number of M2-like macrophages in the tumor microenvironment, and prevented therapy-enhanced tumor metastasis. These findings support continued investigation into the role of MerTK and Efferocytosis in therapeutic tumor responses. Note:This abstract was not presented at the conference. Citation Format: Rebecca S. Cook. Taking out the trash: Efferocytosis in the tumor microenvironment. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr A126.
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Efferocytosis in the tumor microenvironment
Seminars in Immunopathology, 2018Co-Authors: Thomas A Werfel, Rebecca S CookAbstract:Within the course of a single minute, millions of cells in the human body will undergo programmed cell death in response to physiological or pathological cues. The diminished energetic capacity of an apoptotic cell renders the cell incapable of sustaining plasma membrane integrity. Under these circumstances, intracellular contents that might leak into the surrounding tissue microenvironment, a process referred to as secondary necrosis, could induce inflammation and tissue damage. Remarkably, in most cases of physiologically rendered apoptotic cell death, inflammation is avoided because a mechanism to swiftly remove apoptotic cells from the tissue prior to their secondary necrosis becomes activated. This mechanism, referred to as Efferocytosis, uses phagocytes to precisely identify and engulf neighboring apoptotic cells. In doing so, Efferocytosis mantains tissue homeostasis that would otherwise be disrupted by normal cellular turnover and exacerbated further when the burden of apoptotic cells becomes elevated due to disease or insult. Efferocytosis also supports the resolution of inflammation, restoring tissue homesostasis. The importance of Efferocytosis in health and disease underlies the increasing research efforts to understand the mechanisms by which Efferocytosis occurs, and how a failure in the efferocytic machinery contributes to diseases, or conversely, how cancers effectively use the existing efferocytic machinery to generate a tumor-tolerant, immunosuppressive tumor microenvironment. We discuss herein the molecular mechanisms of Efferocytosis, how the process of Efferocytosis might support a tumor ‘wound healing’ phenotype, and efforts to target Efferocytosis as an adjunct to existing tumor treatments.
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Efferocytosis creates a tumor microenvironment supportive of tumor survival and metastasis.
Cancer cell & microenvironment, 2015Co-Authors: David B. Vaught, Jamie C. Stanford, Rebecca S CookAbstract:Programmed cell death, or apoptosis, occurs in nearly all tissues of all multi-cellular organisms. In order to avoid leakage of intracellular contents, which could generate tissue damaging inflammation, apoptotic cells are cleared from tissues by phagocytes, which then dispatch the engulfed dying cell through the lysosomal pathway. Phagocytic clearance of apoptotic cells is referred to as Efferocytosis. One key feature of Efferocytosis is the production and release of wound healing cytokines by the phagocyte, which acts to resolve inflammation, and promote tissue repair. Phagocytic engulfment of apoptotic cells coupled with cytokine modulation aimed at immune suppression ensures that physiological programmed cell death does not induce inflammation and tissue damage. However, cytokines involved in wound healing and immune suppression are notorious for their role in the tumor microenvironment, increasing tumor cell motility and promoting evasion of anti-tumor immunity. Therefore, current and future studies aimed at targeting important players of Efferocytosis should reveal new and efficacious therapeutic approaches for limiting cancer progression and relapse.
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epithelial cell directed Efferocytosis in the post partum mammary gland is necessary for tissue homeostasis and future lactation
BMC Developmental Biology, 2010Co-Authors: Melissa Sandahl, Rebecca S Cook, Debra Hunter, Karen E Strunk, Shelton H EarpAbstract:Background Mammary glands harbor a profound burden of apoptotic cells (ACs) during post-lactational involution, but little is known regarding mechanisms by which ACs are cleared from the mammary gland, or consequences if this process is interrupted. We investigated AC clearance, also termed Efferocytosis, during post-lactational remodeling, using mice deficient for MerTK, Axl, and Tyro3, three related receptor tyrosine kinases (RTKs) regulating macrophage-mediated Efferocytosis in monocytes. MerTK expression, apoptosis and the accumulation of apoptotic debris were examined in histological sections of MerTK-deficient, Axl/Tyro3-deficient, and wild-type mammary glands harvested at specific time points during lactation and synchronized involution. The ability of primary mammary epithelial cells (MECs) to engulf ACs was assessed in culture. Transplant of MerTK-deficient mammary epithelium into cleared WT mammary fat pads was used to assess the contribution of WT mammary macrophages to post-lactational Efferocytosis.
