Match!

Exocytosis of macrophage lysosomes leads to digestion of apoptotic adipocytes and foam cell formation

Published on Jun 1, 2016in Journal of Lipid Research4.74
· DOI :10.1194/jlr.M064089
Abigail S. Haka19
Estimated H-index: 19
(Cornell University),
Valéria C. Barbosa-Lorenzi5
Estimated H-index: 5
(Cornell University)
+ 4 AuthorsFrederick R. Maxfield84
Estimated H-index: 84
(Cornell University)
Cite
Abstract
Many types of apoptotic cells are phagocytosed and digested by macrophages. Adipocytes can be hundreds of times larger than macrophages, so they are too large to be digested by conventional phagocytic processes. The nature of the interaction between macrophages and apoptotic adipocytes has not been studied in detail. We describe a cellular process, termed exophagy, that is important for macrophage clearance of dead adipocytes and adipose tissue homeostasis. Using mouse models of obesity, human tissue, and a cell culture model, we show that macrophages form hydrolytic extracellular compartments at points of contact with dead adipocytes using local actin polymerization. These compartments are acidic and contain lysosomal enzymes delivered by exocytosis. Uptake and complete degradation of adipocyte fragments, which are released by extracellular hydrolysis, leads to macrophage foam cell formation. Exophagy-mediated foam cell formation is a highly efficient means by which macrophages internalize large amounts of lipid, which may ultimately overwhelm the metabolic capacity of the macrophage. This process provides a mechanism for degradation of objects, such as dead adipocytes, that are too large to be phagocytosed by macrophages.
  • References (42)
  • Citations (20)
Cite
References42
Newest
Published on Mar 1, 2016in Journal of Cell Science4.52
Rajesh K. Singh6
Estimated H-index: 6
(Cornell University),
Valéria C. Barbosa-Lorenzi5
Estimated H-index: 5
(Cornell University)
+ 3 AuthorsAbigail S. Haka19
Estimated H-index: 19
(Cornell University)
Monocyte-derived cells use an extracellular, acidic, lytic compartment (a lysosomal synapse) for initial degradation of large objects or species bound to the extracellular matrix. Akin to osteoclast degradation of bone, extracellular catabolism is used by macrophages to degrade aggregates of low density lipoprotein (LDL) similar to those encountered during atherogenesis. However, unlike osteoclast catabolism, the lysosomal synapse is a highly dynamic and intricate structure. In this study, we us...
Published on Sep 1, 2014in Nature Immunology23.53
Stanley Ching-Cheng Huang20
Estimated H-index: 20
(WashU: Washington University in St. Louis),
Bart Everts25
Estimated H-index: 25
(WashU: Washington University in St. Louis)
+ 14 AuthorsChristina M. O'Neill1
Estimated H-index: 1
(WashU: Washington University in St. Louis)
Alternatively activated (M2) macrophages use fatty acid oxidation for their metabolic needs. Pearce and colleagues show that triacylglycerols metabolized by lysosomal acid lipase are required for the M2 activation of and function of macrophages.
Published on Aug 27, 2014in ACS Applied Materials & Interfaces8.46
Ajay Vikram Singh23
Estimated H-index: 23
,
Madu Batuwangala3
Estimated H-index: 3
+ 5 AuthorsW. N. Gade16
Estimated H-index: 16
This study reports a facile biomineralization route for gold microplates (GMPs) synthesis using bovine serum albumin (BSA) as a reductant and stabilizing agent. Adding BSA to HAuCl4 solution yields spontaneous versatile anisotropic and partially hollow GMPs upon aging. We hypothesize that the instantaneous protein denaturation at low pH enabled access to serine and threonine hydroxyl, and sulfhydryl groups of BSA, which act as a reductant and stabilizer, respectively. This reaction could be hast...
Published on Jul 1, 2014in Cell Metabolism22.41
Ingrid Wernstedt Asterholm11
Estimated H-index: 11
(UTSW: University of Texas Southwestern Medical Center),
Caroline Tao10
Estimated H-index: 10
(UTSW: University of Texas Southwestern Medical Center)
+ 4 AuthorsPhilipp E. Scherer111
Estimated H-index: 111
(UTSW: University of Texas Southwestern Medical Center)
Summary Chronic inflammation constitutes an important link between obesity and its pathophysiological sequelae. In contrast to the belief that inflammatory signals exert a fundamentally negative impact on metabolism, we show that proinflammatory signaling in the adipocyte is in fact required for proper adipose tissue remodeling and expansion. Three mouse models with an adipose tissue-specific reduction in proinflammatory potential were generated that display a reduced capacity for adipogenesis i...
Published on Jun 1, 2014in Obesity3.97
Grace Bennett6
Estimated H-index: 6
(Tufts University),
Katherine J. Strissel27
Estimated H-index: 27
(Tufts University)
+ 4 AuthorsMartin S. Obin38
Estimated H-index: 38
(Tufts University)
Objective To investigate the role of TNF-like weak inducer of apoptosis (TWEAK) in pathological adipose tissue (AT) remodeling and complications of obesity. Methods Wild type (WT) and TWEAK knockout (KO) mice were fed normal diet (ND) or a high fat diet (HFD) for up to 17 weeks. Adipocyte death was induced using an established transgenic mouse model of inducible adipocyte apoptosis (FAT-ATTAC). Metabolic, biochemical, histologic, and flow cytometric analyses were performed. Results TWEAK and its...
Published on Dec 1, 2013in Cell Metabolism22.41
Xiaoyuan Xu6
Estimated H-index: 6
(Columbia University),
Ambar Grijalva3
Estimated H-index: 3
(Columbia University)
+ 3 AuthorsAnthony W. Ferrante20
Estimated H-index: 20
(Columbia University)
Summary Obesity activates a complex systemic immune response that includes the recruitment of macrophages and other immune cells to key metabolic tissues. Current models postulate that obesity and excess lipids classically activate macrophages, polarizing them toward an M1 (inflammatory) state. Little is known about noninflammatory functions of adipose tissue macrophages (ATMs). Here, we show that the expansion of adipose tissue (AT) across models of obesity induces a program of lysosome biogene...
Published on Sep 1, 2013in Cell Death & Differentiation8.09
Vitaliya Sagulenko8
Estimated H-index: 8
,
Sara J. Thygesen4
Estimated H-index: 4
+ 9 AuthorsJustine M. Hill17
Estimated H-index: 17
Inflammasomes are protein complexes assembled upon recognition of infection or cell damage signals, and serve as platforms for clustering and activation of procaspase-1. Oligomerisation of initiating proteins such as AIM2 (absent in melanoma-2) and NLRP3 (NOD-like receptor family, pyrin domain-containing-3) recruits procaspase-1 via the inflammasome adapter molecule ASC (apoptosis-associated speck-like protein containing a CARD). Active caspase-1 is responsible for rapid lytic cell death termed ...
Published on Sep 1, 2013in Journal of Lipid Research4.74
Antonio Giordano20
Estimated H-index: 20
(Marche Polytechnic University),
Incoronata Murano18
Estimated H-index: 18
(Marche Polytechnic University)
+ 6 AuthorsSaverio Cinti66
Estimated H-index: 66
(Marche Polytechnic University)
We previously suggested that, in obese animals and humans, white adipose tissue inflammation results from the death of hypertrophic adipocytes; these are then cleared by macrophages, giving rise to distinctive structures we denominated crown-like structures. Here we present evidence that subcutaneous and visceral hypertrophic adipocytes of leptin-deficient (ob/ob and db/db) obese mice exhibit ultrastructural abnormalities (including calcium accumulation and cholesterol crystals), many of which a...
Published on Mar 1, 2013in The Journal of Clinical Endocrinology and Metabolism5.61
Hagit Shapiro16
Estimated H-index: 16
,
Tal Pecht5
Estimated H-index: 5
+ 7 AuthorsAssaf Rudich50
Estimated H-index: 50
(BGU: Ben-Gurion University of the Negev)
Results: ATM lipid content was increased 3-fold in Om compared with SC fat, particularly in obese persons.FCscouldbeidentifiedinsomepatientsandweremostabundantinOmfatofobesepersons, particularly those with intra-abdominal fat distribution. Stepwise multivariate models demonstrated depotdifferentialassociations:fastingglucosewithSCFCs(0.667,P.001)andfastinginsulin( 0.413, P.006) and total ATM count (0.310, P.034) with Om FCs in models including age, body mass index, high-density lipoprotein chole...
Published on Sep 1, 2012in Cell36.22
Nathanael J. Spann19
Estimated H-index: 19
(UCSD: University of California, San Diego),
Lana X. Garmire17
Estimated H-index: 17
(UCSD: University of California, San Diego)
+ 23 AuthorsDaniel Heudobler1
Estimated H-index: 1
(UCSD: University of California, San Diego)
Summary Inflammation and macrophage foam cells are characteristic features of atherosclerotic lesions, but the mechanisms linking cholesterol accumulation to inflammation and LXR-dependent response pathways are poorly understood. To investigate this relationship, we utilized lipidomic and transcriptomic methods to evaluate the effect of diet and LDL receptor genotype on macrophage foam cell formation within the peritoneal cavities of mice. Foam cell formation was associated with significant chan...
Cited By20
Newest
Published on Apr 16, 2019in Journal of Neuroinflammation5.70
Hassan El Hajj4
Estimated H-index: 4
(Laval University),
Julie C. Savage5
Estimated H-index: 5
(Laval University)
+ 4 AuthorsMarie-Ève Tremblay27
Estimated H-index: 27
(Laval University)
Background Alzheimer’s disease (AD) is the most common neurodegenerative disease, characterized by the deposition of extracellular fibrillar amyloid β (fΑβ) and the intracellular accumulation of neurofibrillary tangles. As AD progresses, Aβ drives a robust and prolonged inflammatory response via its recognition by microglia, the brain’s immune cells. Microglial reactivity to fAβ plaques may impair their normal surveillance duties, facilitating synaptic loss and neuronal death, as well as cogniti...
Published on Nov 1, 2019in Molecular metabolism6.18
Yoon Keun Cho , Yeonho Son + 8 AuthorsJames G. Granneman42
Estimated H-index: 42
Abstract Objective This study investigated the role of microRNAs generated from adipose tissue macrophages (ATMs) during adipose tissue remodeling induced by pharmacological and nutritional stimuli. Methods Macrophage-specific Dicer knockout (KO) mice were used to determine the roles of microRNA generated in macrophages in adipose tissue remodeling induced by the β3-adrenergic receptor agonist CL316,243 (CL). RNA-seq was performed to characterize microRNA and mRNA expression profiles in isolated...
Published on 2019in bioRxiv
Tanavi Sharma (PGIMER: Post Graduate Institute of Medical Education and Research), Keshava K. Datta8
Estimated H-index: 8
+ 7 AuthorsNavneet Singla7
Estimated H-index: 7
(PGIMER: Post Graduate Institute of Medical Education and Research)
The scientific basis of intracranial aneurysm (IA) formation, its rupture and further development of cerebral vasospasm remains incompletely understood. Deciphering the molecular mechanisms underlying these events will lead to identification of early detection biomarkers and in turn, improved treatment outcomes. Aberrant protein expression may drive structural alterations of vasculature found in IA. To unravel these aberrations, we performed untargeted, global, quantitative proteomic analysis of...
Published on 2019in Cellular and Molecular Life Sciences7.01
Francesca Riuzzi19
Estimated H-index: 19
(University of Perugia),
Sara Chiappalupi5
Estimated H-index: 5
(University of Perugia)
+ 3 AuthorsRosario Donato45
Estimated H-index: 45
(University of Perugia)
Obesity is an endemic pathophysiological condition and a comorbidity associated with hypercholesterolemia, hypertension, cardiovascular disease, type 2 diabetes mellitus, and cancer. The adipose tissue of obese subjects shows hypertrophic adipocytes, adipocyte hyperplasia, and chronic low-grade inflammation. S100 proteins are Ca2+-binding proteins exclusively expressed in vertebrates in a cell-specific manner. They have been implicated in the regulation of a variety of functions acting as intrac...
Published on Jan 7, 2019in Journal of Crohns & Colitis7.83
Lugen Zuo (Bengbu Medical College), Sitang Ge (Bengbu Medical College)+ 10 AuthorsMulin Liu2
Estimated H-index: 2
(Bengbu Medical College)
Published on Apr 5, 2019in Seminars in Immunopathology6.80
Elise Dalmas (Paris Diderot University)
Growing evidence suggests that components of the innate immune system play a crucial role in regulating metabolic homeostasis. Macrophages were the primary immune cells to be described in both the white adipose tissue and the pancreatic islets. Therein, their functions, beneficial or detrimental, are extending under steady state and in the context of obesity-induced type 2 diabetes. Other populations, including innate lymphoid cells, are emerging as key sentinels of metabolic tissues and privile...
Subothan Inpanathan (RyeU: Ryerson University), Roberto J. Botelho23
Estimated H-index: 23
(RyeU: Ryerson University)
Lysosomes are the terminal degradative compartment of autophagy, endocytosis and phagocytosis. What once was viewed as a simple acidic organelle in charge of macromolecular digestion has emerged as a dynamic organelle capable of integrating cellular signals and producing signal outputs. In this review, we focus on the concept that the lysosome surface serves as a platform to assemble major signaling hubs like mTORC1, AMPK, GSK3 and the inflammasome. These molecular assemblies integrate and facil...
Published on May 1, 2019
Sander Lefere4
Estimated H-index: 4
(UGent: Ghent University),
F. Tacke2
Estimated H-index: 2
(Charité),
F Tacke6
Estimated H-index: 6
(Charité)
Summary Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease worldwide, and a major cause of liver cirrhosis and hepatocellular carcinoma. NAFLD is intimately linked with other metabolic disorders characterized by insulin resistance. Metabolic diseases are driven by chronic inflammatory processes, in which macrophages perform essential roles. The polarization status of macrophages is itself influenced by metabolic stimuli such as fatty acids, which in turn affect the pro...
Published on May 1, 2019in Immunity21.52
Sho Morioka2
Estimated H-index: 2
,
Christian Maueröder , Kodi S. Ravichandran45
Estimated H-index: 45
Summary Nearly every tissue in the body undergoes routine turnover of cells as part of normal healthy living. The majority of these cells undergoing turnover die via apoptosis, and then are rapidly removed by phagocytes by the process of efferocytosis that is anti-inflammatory. However, a number of pathologies have recently been linked to defective clearance of apoptotic cells. Perturbed clearance arises for many reasons, including overwhelming of the clearance machinery, disruptions at differen...
Published on Mar 1, 2019in Nature Reviews Endocrinology24.65
Daniela F. Quail12
Estimated H-index: 12
(McGill University),
Andrew J. Dannenberg82
Estimated H-index: 82
(Cornell University)
Obesity is associated with both increased cancer incidence and progression in multiple tumour types, and is estimated to contribute to up to 20% of cancer-related deaths. These associations are driven, in part, by metabolic and inflammatory changes in adipose tissue that disrupt physiological homeostasis both within local tissues and systemically. However, the mechanisms underlying the obesity–cancer relationship are poorly understood. In this Review, we describe how the adipose tissue microenvi...
View next paperAdipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans