Efferocytosis Modulates Arginase-1 and Tyrosine Kinase Mer Expression in GM-CSF-Differentiated Human Macrophages

Сахно, Л. В.; Shevela, Е. Ya.; Тихонова, М. А.; Максимова, Анастасия Алексеевна; Тыринова, Т. В.; Останин, А. А.; Черных, Е. Р.

doi:10.1007/s10517-021-05153-z

Cited by 6 publications

(3 citation statements)

References 12 publications

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“…Murine GM-CSF-induced bone marrow-derived macrophages express MerTK receptors and exhibit high phagocytic ability ( 97 ). Human macrophages differentiated with GM-CSF from healthy adult monocyte samples, and which were cultured either under growth/serum factor deficiency, or with subsequent treatment of IL-4 or incubation with apoptotic cells, result in M2-polarized macrophages that exhibit increased MerTK expression ( 98 ). Finally, activated peroxisome proliferator-activated receptor (PPAR)-γ and liver X receptor (LXR)-α drive anti-inflammatory macrophage engulfment of apoptotic cells ( 91 ).…”

Section: Emerging Biology Of Gm-csfmentioning

confidence: 99%

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

Lazarus

Pitts²,

Wang

et al. 2023

Front. Immunol.

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IntroductionEndogenous granulocyte-macrophage colony-stimulating factor (GM-CSF), identified by its ability to support differentiation of hematopoietic cells into several types of myeloid cells, is now known to support maturation and maintain the metabolic capacity of mononuclear phagocytes including monocytes, macrophages, and dendritic cells. These cells sense and attack potential pathogens, present antigens to adaptive immune cells, and recruit other immune cells. Recombinant human (rhu) GM-CSF (e.g., sargramostim [glycosylated, yeast-derived rhu GM-CSF]) has immune modulating properties and can restore the normal function of mononuclear phagocytes rendered dysfunctional by deficient or insufficient endogenous GM-CSF.MethodsWe reviewed the emerging biologic and cellular effects of GM-CSF. Experts in clinical disease areas caused by deficient or insufficient endogenous GM-CSF examined the role of GM-CSF in mononuclear phagocyte disorders including autoimmune pulmonary alveolar proteinosis (aPAP), diverse infections (including COVID-19), wound healing, and anti-cancer immune checkpoint inhibitor therapy.ResultsWe discuss emerging data for GM-CSF biology including the positive effects on mitochondrial function and cell metabolism, augmentation of phagocytosis and efferocytosis, and immune cell modulation. We further address how giving exogenous rhu GM-CSF may control or treat mononuclear phagocyte dysfunction disorders caused or exacerbated by GM-CSF deficiency or insufficiency. We discuss how rhu GM-CSF may augment the anti-cancer effects of immune checkpoint inhibitor immunotherapy as well as ameliorate immune-related adverse events.DiscussionWe identify research gaps, opportunities, and the concept that rhu GM-CSF, by supporting and restoring the metabolic capacity and function of mononuclear phagocytes, can have significant therapeutic effects. rhu GM-CSF (e.g., sargramostim) might ameliorate multiple diseases of GM-CSF deficiency or insufficiency and address a high unmet medical need.

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Section: Emerging Biology Of Gm-csfmentioning

confidence: 99%

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

Lazarus

Pitts²,

Wang

et al. 2023

Front. Immunol.

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“…For Arg-1, the efferocytosis of apoptotic neutrophils significantly promotes M2 macrophage polarization, as well as increased expression of Arg-1 and MerTK (Sakhno et al, 2021). Impairing efferocytosis through the depletion of protein S could result in decreased expression levels of Arg-1, 12/15LOX and Resolvin D1 (Lumbroso et al, 2020).…”

Section: Targeting Other Proresolving Mediatorsmentioning

confidence: 99%

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

Zhang

Ding

Zhao

et al. 2022

British J Pharmacology

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Efferocytosis is defined as the clearance of apoptotic cells (ACs) in physiological and pathological states and is performed by efferocytes, such as macrophages. Efferocytosis can lead to the resolution of inflammation and restore tissue homoeostasis; however, the mechanisms of efferocytosis in determining inflammation resolution are still not completely understood, and the effects of efferocytosis on other proresolving properties need to be explored and explained. In this review, the process of efferocytosis will be summarized briefly, and then these mechanisms and effects will be thoroughly discussed. In addition, the association between mechanisms of efferocytosis in determining resolution of inflammation and cardiovascular diseases will also be reviewed, as an understanding of this association may provide information on novel treatment targets. | INTRODUCTIONIn an adult human, billions of cells die and turn over every day. During this process, a large number of apoptotic cells (ACs) are produced and subsequently cleared by phagocytes, a process termed efferocytosis, which plays a critical role in the maintenance of tissue homeostasis in physiology (Doran et al., 2020). In addition, a large number of cells also die in pathological conditions, such as acute myocardial infarction (AMI), and appropriate efferocytosis is necessary. The failure of the process of efferocytosis leads to the accumulation of ACs, which in turn leads to the formation of a secondary necrotic core and the release of inflammatory cytokines and chemokines, thus contributing to the development of autoimmune diseases, inflammatory diseases and dampened restoration of repair (Elliott et al., 2017;Tajbakhsh et al., 2019).Mechanistically, efferocytosis is distinct from classic forms of phagocytosis. Professional (macrophages, dendritic cells) and nonprofessional phagocytes recognize AC-expressed ligands via specialized

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“…Macrophages are essential cellular components of both early and advanced atherosclerotic lesions. Polarization of macrophages toward a proinflammatory phenotype, which produces high levels of IL-2, IL-23, IL-6, IL-1β, and TNFα, is strongly associated with atherosclerosis, whereas proresolving macrophages, which produce large amounts of IL-10 and Transforming growth factor beta (TGFβ) as well as expressing scavenger receptors, mannose receptors, and arginase 1 (Arg1), have been linked to atherosclerosis regression [11][12][13][14][15] . Consistently, proinflammatory macrophages show impairments in efferocytosis, while proresolving macrophages efficiently consume ACs [8,9] .…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of continual efferocytosis by macrophages and its role in mitigating atherosclerosis

2023

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Atherosclerotic cardiovascular disease is the leading cause of death worldwide. Rupture-prone atheromas that give rise to myocardial infarction and stroke are characterized by the presence of a necrotic core and a thin fibrous cap. During homeostasis, cellular debris and apoptotic cells are cleared quickly through a process termed “efferocytosis”. However, clearance of apoptotic cells is significantly compromised in many chronic inflammatory diseases, including atherosclerosis. Emerging evidence suggests that impairments in efferocytosis drive necrotic core formation and contribute significantly to plaque vulnerability. Recently, it has been appreciated that successive rounds of efferocytosis, termed “continual efferocytosis”, is mechanistically distinct from single efferocytosis and relies heavily on the metabolism and handling of apoptotic cell-derived cargo. In vivo, selective defects in continual efferocytosis drive secondary necrosis, impair inflammation resolution, and worsen atherosclerosis. This Mini Review focuses on our current understanding of the cellular and molecular mechanisms of continual efferocytosis and how dysregulations in this process mediate nonresolving inflammation. We will also discuss possible strategies to enhance efferocytosis when it fails.

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Efferocytosis Modulates Arginase-1 and Tyrosine Kinase Mer Expression in GM-CSF-Differentiated Human Macrophages

Cited by 6 publications

References 12 publications

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders

Mechanisms of efferocytosis in determining inflammation resolution: Therapeutic potential and the association with cardiovascular disease

Mechanisms of continual efferocytosis by macrophages and its role in mitigating atherosclerosis

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