Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury

Yurdagul, Arif; Subramanian, Manikandan; Wang, Xiaobo; Crown, Scott B.; Ilkayeva, Olga; Darville, Lancia; Kolluru, Gopi K.; Rymond, Christina C.; Gerlach, Brennan D.; Zheng, Ze; Kuriakose, George; Kevil, Christopher G.; Koomen, John M.; Cleveland, John L.; Muoio, Deborah M.; Tabas, Ira

doi:10.1016/j.cmet.2020.01.001

Cited by 306 publications

(341 citation statements)

References 70 publications

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“…S3f) nor the newly identified Rac1 transcriptional regulator GTP-exchange factor Dbl was affected ( Fig. S3g) (Yurdagul et al, 2020). Similar gene expression of polymerization/depolymerization regulators was also observed (Fig.…”

Section: Introductionsupporting

confidence: 65%

“…Thus, glutaminolysis does not control the transcriptional efferocytic reprograming in reparative macrophages. To next distinguish whether defective glutaminolysis impact AC binding or internalization, we incubated macrophages with cytochalasin D, an actin polymerization inhibitor (Yurdagul et al, 2020). In the cytochalasin D-treated cells, macrophage-AC association was similar among control and reparative Mac ΔGls1 BMDMs (Fig.…”

Section: Introductionmentioning

confidence: 97%

“…Clearance of apoptotic cells (ACs) by macrophages (i.e, efferocytosis) prevent the leakage of dying cellular contents to maintain tissue integrity in normal physiology (Kojima et al, 2017;Elliott and Ravichandran, 2016). Impaired efferocytosis in disease can have multiple causes, but defects in the internalization of multiple ACs, a process termed 'continual efferocytosis', has emerged as a culprit of many chronic inflammatory diseases such as atherosclerosis (Wang et al, 2017;Yurdagul et al, 2020). Resolution and repair processes also require the cytokine interleukin-4 (IL-4) (Bosurgi et al, 2017) and an efficient cellular metabolic reprogramming to sustain continual efferocytosis (Han and Ravichandran, 2011).…”

Section: Introductionmentioning

confidence: 99%

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Non-canonical glutamine transamination metabolism sustains efferocytosis by coupling oxidative stress buffering to oxidative phosphorylation

Merlin¹,

Ivanov²,

Dumont³

et al. 2020

Preprint

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Macrophages rely on tightly integrated metabolic rewiring to clear dying neighboring cells by efferocytosis during homeostasis and disease. Here, we reveal glutaminase (Gls) 1-mediated glutaminolysis is critical to promote apoptotic cell clearance by macrophages during homeostasis. In addition, impaired macrophage glutaminolysis exacerbated atherosclerosis, a condition during which efficient apoptotic cell debris clearance is critical to limit disease progression. Gls1 expression strongly correlated with atherosclerotic plaque necrosis in patients with cardiovascular diseases. High-throughput transcriptional and metabolic profiling revealed that macrophage efferocytic capacity rely on a non-canonical transaminase pathway, independent from the traditional requirement of glutamate dehydrogenase (Glud1) to fuel ɑ-ketogulatrate-dependent immunometabolism. This pathway was necessary to meet the unique requirements of efferocytosis for cellular detoxification and high energy cytoskeletal rearrangements. Thus, we uncovered a novel role for non-canonical glutamine metabolism for efficient clearance of dying cells and maintenance of tissue homeostasis during health and disease.

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Section: Introductionsupporting

confidence: 65%

Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Non-canonical glutamine transamination metabolism sustains efferocytosis by coupling oxidative stress buffering to oxidative phosphorylation

Merlin¹,

Ivanov²,

Dumont³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Exogenous administration of putrescine increases inflammation resolution in the context of atherosclerosis. Consistently, deficiency in myeloid cells of either the enzyme arginase 1 (Arg1), which converts arginine to ornithine, or the enzyme ornithine decarboxylase (ODC), which mediates the decarboxylation of ornithine to putrescine (Figure 2), is associated with efferocytic dysfunction and defective atherosclerosis resolution (105).…”

Section: Metabolic Modulation Of Macrophage Function In the Context Omentioning

confidence: 94%

“…Upon efferocytosis, increased glucose uptake via upregulated SLC2A1 and enhanced glycolysis are linked with enhanced lactate release via SLC16A (102). The metabolism of arginine and ornithine to putrescine is involved in promoting continual efferocytosis (105). In addition, enhanced lipid metabolism upon efferocytosis is associated with fatty acid oxidation and Sirtuin 1 (Sirt1)-dependent upregulation of IL-10 (18).…”

Section: Molecular Cross-talk Between Apoptotic Cells and Macrophagesmentioning

confidence: 99%

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

2020

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Efficient inflammation resolution is important not only for the termination of the inflammatory response but also for the restoration of tissue integrity. An integral process to resolution of inflammation is the phagocytosis of dying cells by macrophages, known as efferocytosis. This function is mediated by a complex and well-orchestrated network of interactions amongst specialized phagocytic receptors, bridging molecules, as well as "find-me" and "eat-me" signals. Efferocytosis serves not only as a waste disposal mechanism (clearance of the apoptotic cells) but also promotes a pro-resolving phenotype in efferocytic macrophages and thereby termination of inflammation. Alterations in cellular metabolism are critical for shaping the phenotype and function of efferocytic macrophages, thus, representing an important determinant of macrophage plasticity. Impaired efferocytosis can result in inflammation-associated pathologies or autoimmunity. The present mini review summarizes current knowledge regarding the mechanisms regulating macrophage efferocytosis during clearance of inflammation.

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Constructing Mal‐Efferocytic Macrophage Model and Its Atherosclerotic Spheroids and Rat Model for Therapeutic Evaluation

et al. 2023

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Efferocytosis, responsible for apoptotic cell clearance, is an essential factor against atherosclerosis. It is reported that efferocytosis is severely impaired in fibroatheroma, especially in vulnerable thin cap fibroatheroma. However, there is a shortage of studies on efferocytosis defects in cell and animal models. Here, the impacts of oxidized low density lipoprotein (ox‐LDL) and glut 1 inhibitor (STF31) on efferocytosis of macrophages are studied, and an evaluation system is constructed. Through regulating the cell ratios and stimulus, three types of atherosclerotic spheroids are fabricated, and a necrotic core emerges with surrounding apoptotic cells. Rat models present a similar phenomenon in that substantial apoptotic cells are uncleared in time in vulnerable plaque, and the model period is shortened to 7 weeks. Mechanism studies reveal that ox‐LDL, through mRNA and miRNA modulation, downregulates efferocytosis receptor (PPARγ/LXRα/MerTK), internalization molecule (SLC29a1), and upregulates the competitive receptor CD300a that inhibits efferocytosis receptor‐ligand binding process. The foam cell differentiation has also confirmed that CD36 and Lp‐PLA2 levels are significantly elevated, and macrophages present an interesting transition into prothrombic phenotype. Collectively, the atherosclerotic models featured by efferocytosis defect provide a comprehensive platform to evaluate the efficacy of medicine and biomaterials for atherosclerosis treatment.

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Macrophage Metabolism of Apoptotic Cell-Derived Arginine Promotes Continual Efferocytosis and Resolution of Injury

Cited by 306 publications

References 70 publications

Non-canonical glutamine transamination metabolism sustains efferocytosis by coupling oxidative stress buffering to oxidative phosphorylation

Non-canonical glutamine transamination metabolism sustains efferocytosis by coupling oxidative stress buffering to oxidative phosphorylation

Phagocytosis of Apoptotic Cells in Resolution of Inflammation

Constructing Mal‐Efferocytic Macrophage Model and Its Atherosclerotic Spheroids and Rat Model for Therapeutic Evaluation

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