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Delphine Lumbroso, Soaad Soboh, Avi Maimon, Sagie Schif-Zuck, Amiram Ariel, Tal Burstyn-Cohen
The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL, and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood...
2018: Frontiers in Immunology
Yung-Che Chen, Meng-Chih Lin, Chih-Hung Lee, Shih-Feng Liu, Chin-Chou Wang, Wen-Feng Fang, Tung-Ying Chao, Chao-Chien Wu, Yu-Feng Wei, Huang-Chih Chang, Chia-Cheng Tsen, Hung-Chen Chen
BACKGROUND: Controversy exists in previous studies on macrophage M1/M2 polarization in chronic obstructive pulmonary disease (COPD). We hypothesized that formyl peptide receptor (FPR), a marker of efferocytosis and mediator of M1/M2 polarization, may be involved in the development of COPD. METHODS: We examined FPR 1/2/3 expressions of blood M1/M2a monocyte, neutrophil, natural killer (NK) cell, NK T cell, T helper (Th) cell, and T cytotoxic (Tc) cell by flowcytometry method in 40 patients with cigarette smoking-related COPD and 16 healthy non-smokers...
March 15, 2018: Journal of Translational Medicine
Ana Hernández, Paula Arbildi, Cecilia Sóñora, Natalia Del Río, Juan Martin Marques
Tissue transglutaminase is a ubiquitous and multifunctional protein that contribute to several processes such as apoptosis/survival, efferocytosis, inflammation and tissue repairing under physiological and pathological conditions. Several activities can be associated with well established functional domains; in addition, four RNA alternative splice variants have been described, characterized by sequence divergences and residues deletion at the C-terminal domains Tissue transglutaminase is recognized as the central player in the physiopathology of celiac disease mainly through calcium dependent enzymatic activities...
March 15, 2018: Scandinavian Journal of Immunology
Manon Viaud, Stoyan Ivanov, Nemanja Vujic, Madalina Duta-Mare, Lazaro-Emilio Aira, Thibault Barouillet, Elsa Garcia, François Orange, Isabelle Dugail, Isabelle Hainault, Christian Stehlik, Sandrine Marchetti, Laurent Boyer, Rodolphe Guinamard, Fabienne Foufelle, Andrea E Bochem, Kees G Hovingh, Edward B Thorp, Emmanuel L Gautier, Dagmar Kratky, Paul A Da Silva-Jardine, Laurent Yvan-Charvet
<u>Rationale:</u> Macrophages face a substantial amount of cholesterol following the ingestion of apoptotic cells and the lysosomal acid lipase (LIPA) has a major role in hydrolyzing cholesteryl esters in the endocytic compartment. <u>Objective:</u> Here, we directly investigated the role of LIPA-mediated clearance of apoptotic cells both in vitro and in vivo. <u>Methods and Results:</u> We show that LIPA inhibition causes a defective efferocytic response due to impaired generation of 25-OHC and 27-OHC...
March 9, 2018: Circulation Research
Bridget Shafit-Zagardo, Ross C Gruber, Juwen C DuBois
Tyro3, Axl, and Mertk, referred to as the TAM family of receptor tyrosine kinases, are instrumental in maintaining cell survival and homeostasis in mammals. TAM receptors interact with multiple signaling molecules to regulate cell migration, survival, phagocytosis and clearance of metabolic products and cell debris called efferocytosis. The TAMs also function as rheostats to reduce the expression of proinflammatory molecules and prevent autoimmunity. All three TAM receptors are activated in a concentration-dependent manner by the vitamin K-dependent growth arrest-specific protein 6 (Gas6)...
March 4, 2018: Pharmacology & Therapeutics
Oliver H Voss, Ha-Na Lee, Linjie Tian, Konrad Krzewski, John E Coligan
Efficient phagocytosis of apoptotic cells (efferocytosis) is essential for immune homeostasis. Phospholipids exposed on the surface of apoptotic cells, such as phosphatidylserine, supply important "eat-me" signals. Liposomes are lipid bilayer vesicles that can be generated from one or several types of phospholipids of interest. Thus, these vesicles offer versatility, flexibility, and, importantly, a three-dimensional structure for studying the interaction between lipids and their receptors as well as the lipid-receptor interaction-mediated signaling events controlling efferocytosis by cells like professional phagocytes...
February 21, 2018: Current Protocols in Immunology
Myeong-Joo Kim, Ye-Ji Lee, Young-So Yoon, Jae H Lim, Eun-Mi Park, Young H Chong, Jihee Lee Kang
BACKGROUND/AIMS: The signal transducer and activator of transcription 6 (STAT6) transcription factor mediates PPARγ-regulated gene expression in macrophages. However, it remains largely unknown how proximal membrane signaling events initiated by apoptotic cell recognition upregulate PPARγ expression and activate the lung homeostatic program. METHODS: The STAT6 inhibitor AS1517499 was used to determine the role of STAT6 in mediating PPARγ activity, anti-inflammatory effects, and anti-fibrotic effects induced by apoptotic cell instillation after bleomycin treatment into C57BL/6 mice...
February 28, 2018: Cellular Physiology and Biochemistry
Yan-Ran Sheng, Wen-Ting Hu, Chun-Yan Wei, Ling-Li Tang, Yu-Kai Liu, Yu-Yin Liu, Jian-Ping Qiu, Da-Jin Li, Xiao-Yong Zhu
PROBLEM: To explore whether IL-33/ST2 axis modulates the polarization and efferocytosis of decidual macrophages (dMφs). METHOD OF STUDY: The phenotype characteristics of dMφs from both normal pregnant women and recurrent spontaneous abortion (RSA) patients were determined by real-time polymerase chain reaction (RT-PCR) and flow cytometry (FCM). Then, the efferocytosis and expression of IL-33 and its receptor (ST2) in dMφs were analyzed by FCM. Finally, the effects of sST2, a decoy receptor for IL-33 that inhibits the IL-33/ST2 signaling pathway, on the polarization and efferocytosis of dMφs and human macrophage cell line U937 were investigated...
March 3, 2018: American Journal of Reproductive Immunology: AJRI
Silvia Rodriguez-Fernandez, Irma Pujol-Autonell, Ferran Brianso, David Perna-Barrull, Mary Cano-Sarabia, Sonia Garcia-Jimeno, Adrian Villalba, Alex Sanchez, Eva Aguilera, Federico Vazquez, Joan Verdaguer, Daniel Maspoch, Marta Vives-Pi
Type 1 diabetes (T1D) is a metabolic disease caused by the autoimmune destruction of insulin-producing β-cells. With its incidence increasing worldwide, to find a safe approach to permanently cease autoimmunity and allow β-cell recovery has become vital. Relying on the inherent ability of apoptotic cells to induce immunological tolerance, we demonstrated that liposomes mimicking apoptotic β-cells arrested autoimmunity to β-cells and prevented experimental T1D through tolerogenic dendritic cell (DC) generation...
2018: Frontiers in Immunology
Amir Tajbakhsh, Mehdi Rezaee, Petri T Kovanen, Amirhossein Sahebkar
Atherosclerosis is a dynamic and progressive inflammatory process in the intimal layer of large and medium-sized arteries, and it is the major contributor to the atherosclerotic cardiovascular disease (ACVD), the leading cause of death worldwide. In an atherosclerotic plaque, phagocytosis of apoptotic cells occurs through an intricate process designated efferocytosis. Defective efferocytosis has emerged as a causal factor in the etiopathogenesis of atherosclerosis and its progression into overt ACVD. Both specialized phagocytes (macrophages and dendritic cells) and non-specialized cells with phagocytic capabilities (smooth muscle and endothelial cells) are involved in the efferocytotic process...
February 11, 2018: Pharmacology & Therapeutics
Siamon Gordon, Annette Plüddemann
As the body continues to grow and age, it becomes essential to maintain a balance between living and dying cells. Macrophages and dendritic cells play a central role in discriminating among viable, apoptotic, and necrotic cells, as selective and efficient phagocytes, without inducing inappropriate inflammation or immune responses. A great deal has been learnt concerning clearance receptors for modified and non-self-ligands on potential targets, mediating their eventual uptake, disposal, and replacement. In this essay, we assess current understanding of the phagocytic recognition of apoptotic cells within their tissue environment; we conclude that efferocytosis constitutes a more complex process than simply removal of corpses, with regulatory interactions between the target and effector cells, which determine the outcome of this homeostatic process...
2018: Frontiers in Immunology
Li Zhang
PURPOSE OF REVIEW: Macrophages are generally believed to originate entirely from the bone marrow; however, this paradigm is challenged by the discovery of yolk-sac-derived resident macrophages. Here, we provide an overview of recent advances in the ontogeny and function of resident macrophages. RECENT FINDINGS: Macrophage precursors from three distinct embryonic sources (yolk sac, fetal liver and bone marrow) are found to colonize various tissues via the blood circulation early during embryogenesis until shortly after birth...
February 12, 2018: Current Opinion in Hematology
Giselle S Magalhaes, Lívia C Barroso, Alesandra C Reis, Maria G Rodrigues-Machado, Juliana F Gregório, Daisy Motta-Santos, Aline C Oliveira, Denise A Perez, Lucíola S Barcelos, Mauro M Teixeira, Robson A S Santos, Vanessa Pinho, Maria Jose Campagnole-Santos
Defective apoptosis of eosinophils, the main leukocyte in the pathogenesis of asthma, and delay in its removal lead to lung damage and loss of pulmonary function due to failure in the resolution of inflammation. Here, we investigated the ability of angiotensin-(1-7) [Ang-(1-7)], a pivotal peptide of the renin-angiotensin system, to promote resolution of an allergic lung inflammatory response. Balb/c mice were sensitized and challenged with ovalbumin and treated with Ang-(1-7) at the peak of the inflammatory process...
2018: Frontiers in Immunology
Jennifer M Felton, Christopher D Lucas, David A Dorward, Rodger Duffin, Tiina Kipari, Sonja Vermeren, Calum T Robb, Kenneth G MacLeod, Bryan Serrels, Jürgen Schwarze, Christopher Haslett, Ian Dransfield, Adriano G Rossi
BACKGROUND: Eosinophils play a central role in the propagation of allergic diseases including asthma. Both recruitment and retention of eosinophils regulate pulmonary eosinophilia but the question of whether alterations in apoptotic cell clearance by phagocytes directly contributes to resolution of allergic airway inflammation remains unexplored. OBJECTIVES: In this study we investigated the role of the receptor tyrosine kinase Mer in mediating apoptotic eosinophil clearance and allergic airway inflammation resolution in vivo in order to establish whether apoptotic cell clearance directly impacts upon the resolution of allergic airway inflammation...
February 8, 2018: Journal of Allergy and Clinical Immunology
Scott P Davies, Gary M Reynolds, Zania Stamataki
Toxic substances and microbial or food-derived antigens continuously challenge the liver, which is tasked with their safe neutralization. This vital organ is also important for the removal of apoptotic immune cells during inflammation and has been previously described as a "graveyard" for dying lymphocytes. The clearance of apoptotic and necrotic cells is known as efferocytosis and is a critical liver function to maintain tissue homeostasis. Much of the research into this form of immunological control has focused on Kupffer cells, the liver-resident macrophages...
2018: Frontiers in Immunology
Joo-Young Kim, Young-Mi Kim, Jong-Min Park, Young Min Han, Kang Choon Lee, Ki Baik Hahm, Suntaek Hong
The potential of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in inducing apoptosis is a hallmark in cancer therapeutics, after which its selective ability to achieve cell death pathways against cancer cells led to hope for recombinant TRAIL in cancer therapeutics. The present data from azoxymethane-initiated, dextran sulfate sodium-promoted colitis associated cancer (CAC) model strongly indicate the potential of rTRAIL in cancer prevention rather than in cancer therapeutics. Early treatment of rTRAIL significantly reduced colitis and CAC by inhibiting the recruitment of macrophages into the damaged mucosa and activating the scavenger activity with efferocytosis and the production of several growth factors...
January 5, 2018: Oncotarget
Ankita Solanki, Lokesh Kumar Bhatt, Thomas P Johnston
Atherosclerosis is a progressive disease of large arteries and a leading cause of cardiovascular diseases and stroke. Chronic inflammation, aberrant immune response, and disturbances to key enzymes involved with lipid metabolism are characteristic features of atherosclerosis. Apart from targeting the derangements in lipid metabolism, therapeutic modulation to regulate chronic inflammation and the immune system response may prove to be very promising strategies in the management of atherosclerosis. In recent years, various targets have been studied for the treatment of atherosclerosis...
February 4, 2018: Pharmacology & Therapeutics
Meng Wang, S Courtney Frasch, Guiying Li, Dechun Feng, Bin Gao, Liangguo Xu, Diana Ir, Daniel N Frank, Donna L Bratton, Cynthia Ju
Hepatic macrophages (M Φ s) are important in the development and progression of alcoholic liver disease (ALD). This study investigates the role of gp91phox(nicotinamide adenine dinucleotide phosphate oxidase 2) in the severity of ALD and specifically in regulating hepatic M Φ efferocytic capability and the subsequent reprogramming associated with resolution of inflammation. After 4 weeks of ethanol feeding, more severe ALD developed in gp91phox-/-mice than in wild-type (WT) C57Bl/6J mice, evidenced by increased liver injury and inflammation...
October 2017: Hepatology Communications
Aleksander M Grabiec, Anu Goenka, Mark E Fife, Toshifumi Fujimori, Tracy Hussell
The requirement to remove apoptotic cells is equally important in homeostasis and inflammatory disease. In particular, during viral infections large quantities of infected cells undergo apoptosis and need to be efficiently cleared by phagocytes to prevent secondary necrosis. Although specific roles of several apoptotic cell sensors, such as the TAM (Tyro3, Axl, MerTK) receptor family, have been characterized in mouse models, little is known about their regulation and involvement in apoptotic cell uptake (efferocytosis) by human macrophages under inflammatory conditions...
February 5, 2018: European Journal of Immunology
Trent D Evans, Se-Jin Jeong, Xiangyu Zhang, Babak Razani
In the atherosclerotic plaque, macrophages are the key catabolic workhorse responsible for clearing lipid and dead cell debris. To survive the highly proinflammatory and lipotoxic plaque environment, macrophages must adopt strategies for maintaining tight homeostasis and self-renewal. Macroautophagy/autophagy is a pro-survival cellular pathway wherein damaged or excess cellular cargoes are encapsulated by a double-membrane compartment and delivered to the lysosome for hydrolysis. Previously, macrophage-specific autophagy deficiency has been shown to be atherogenic through several complementary mechanisms including hyperactivation of the inflammasome, defective efferocytosis, accumulation of cytotoxic protein aggregates, and impaired lipid degradation...
February 2, 2018: Autophagy
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