The clearance of dead cells by efferocytosis

Boada-Romero, Emilio; Martinez, Jennifer; Heckmann, Bradlee L.; Green, Douglas R.

doi:10.1038/s41580-020-0232-1

Cited by 514 publications

(504 citation statements)

References 256 publications

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“…Poor clearance and accumulation of dead cells has been extensively reported in diseases of chronic inflammation ( 76 , 77 ) and autoimmunity ( 78 – 81 ), suggesting that effective efferocytosis of cell death corpses from multiple death mechanisms is essential for the maintenance of tissue homeostasis ( 27 , 82 ). Ingestion of apoptotic cells by phagocytes prevents release of their intracellular contents therefore precluding inflammation ( 19 ).…”

Section: Discussionmentioning

confidence: 99%

“…cSiO 2 exposure induces AM death by apoptosis, pyroptosis, and necrosis ( 16 , 25 , 26 ). In addition, AM play essential roles in efferocytosis of dead and dying cells from the lung to prevent untoward inflammatory and immune responses ( 27 ). By clearing the cell corpses, AMs limit inflammation and prevent secondary necrosis of apoptotic cells ( 28 , 29 ).…”

Section: Introductionmentioning

confidence: 99%

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Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis

et al. 2020

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Airway exposure of lupus-prone NZBWF1 mice to crystalline silica (cSiO 2 ), a known trigger of human autoimmune disease, elicits sterile inflammation and alveolar macrophage death in the lung that, in turn, induces early autoimmune onset and accelerates lupus progression to fatal glomerulonephritis. Dietary supplementation with docosahexaenoic acid (DHA), a marine ω-3 polyunsaturated fatty acid (PUFA), markedly ameliorates cSiO 2 -triggered pulmonary, systemic, and renal manifestations of lupus. Here, we tested the hypothesis that DHA influences both cSiO 2 -induced death and efferocytotic clearance of resultant cell corpses using three murine macrophage models: (i) primary alveolar macrophages (AM) isolated from NZBWF1 mice; (ii) self-renewing AM-like Max Planck Institute (MPI) cells isolated from fetuses of C57BL/6 mice, and (iii) RAW 264.7 murine macrophages, a virus-transformed cell line derived from BALB/c mice stably transfected with the inflammasome adaptor protein ASC (RAW-ASC). Incubation with cSiO 2 at 25 and 50 μg/ml for 6 h was found to dose-dependently induce cell death ( p < 0.05) in all three models as determined by both acridine orange/propidium iodide staining and release of lactate dehydrogenase into cell culture supernatant. Pre-incubation with DHA at a physiologically relevant concentration (25 μM) significantly reduced cSiO 2 -induced death ( p < 0.05) in all three models. Cell death induction by cSiO 2 alone and its suppression by DHA were primarily associated with caspase-3/7 activation, suggestive of apoptosis, in AM, MPI, and RAW-ASC cells. Fluorescence microscopy revealed that all three macrophage models were similarly capable of efferocytosing RAW-ASC target cell corpses. Furthermore, MPI effector cells could likewise engulf RAW-ASC target cell corpses elicited by treatment with staurosporine (apoptosis), LPS, and nigericin (pyroptosis), or cSiO 2 . Pre-incubation of RAW-ASC target cells with 25 μM DHA prior to death induced by these agents significantly enhanced their efferocytosis ( p < 0.05) by MPI effector cells. In contrast, pre-incubating MPI effector cells with DHA did not affect engulfment of RAW-ASC target cells pre-incubated with vehicle. Taken together, these findings indicate that DHA at a physiologically relevant concentration was capable of attenuating macrophage death and could potentiate efferocytosis, with the net effect of reducing accumulation of cell corpses capable of eliciting autoimmunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis

et al. 2020

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“…The RPE-mediated OS non-inflammatory clearance process requires LC3-associated phagocytosis. Deficiency in LAP has been associated with various disorders such as SLE, multiple sclerosis, atherosclerosis, and AMD, amongst others 40 . It has proven quite challenging to study AMD, since mouse models of genetically validated targets do not recapitulate the human phenotype.…”

Section: Discussionmentioning

confidence: 99%

Loss of CIB2 causes non-canonical autophagy deficits and visual impairment

Sethna

Scott

Giese

et al. 2020

Preprint

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SUMMARYNon-canonical autophagy or LC3-associated phagocytosis (LAP) is essential for the maintenance and functioning of the retinal pigment epithelium (RPE) and photoreceptors. Although molecular mechanisms still remain elusive, deficits in LAP have been found to be associated with age-related retinal pathology in both mice and humans. In this study, we found that calcium and integrin-binding protein 2 (CIB2) regulates LAP in the RPE. Mice lacking CIB2, both globally and specifically within RPE, have an impaired ability to process the engulfed photoreceptor outer segments due to reduced lysosomal capacity, which leads to marked accumulation of improperly digested remnants, lipid droplets, fused phago-melanosomes in RPE, and impaired visual function. In aged mice, we also found marked accumulation of drusen markers APOE, C3, and Aβ, along with esterified cholesterol. Intriguingly, we were able to transiently rescue the photoreceptor function in Cib2 mutant mice by exogenous retinoid delivery. Our study links LAP and phagocytic clearance with CIB2, and their relevance to the sense of sight.

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“…In the case of mitochondrial fission, these studies showed that mitochondrial fission allows for an increase in cellular calcium and subsequent phagosome maturation and the tolerogenic signals associated with efferocytosis [ 72 ]. Finally, recent studies showed that in LC3-associated phagocytosis (LAP), in which autophagy proteins are involved apoptotic cell clearance, phagosome formation and maturation is required for tolerogenic signals such as IL-10 production and immune silencing [ 73 , 74 ]. Indeed, a common theme in PS biology and PS-dependent efferocytosis is that final degradation of the corpses is generally immunosuppressive and tolerogenic, and physiological efferocytosis has been shown to suppress the production of pro-inflammatory factors, such as TNF-α; induce the production of immunosuppressive factors, such as IL-10; and induce pro-resolving factors and lipoxins, as well as inhibit the generation of ROS and NF-kB.…”

Section: Physiological Signals From Efferocytosis In Normal Tissuementioning

confidence: 99%

Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy

Gadiyar

Lahey

Calianese

et al. 2020

Cells

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The physiological fate of cells that die by apoptosis is their prompt and efficient removal by efferocytosis. During these processes, apoptotic cells release intracellular constituents that include purine nucleotides, lysophosphatidylcholine (LPC), and Sphingosine-1-phosphate (S1P) that induce migration and chemo-attraction of phagocytes as well as mitogens and extracellular membrane-bound vesicles that contribute to apoptosis-induced compensatory proliferation and alteration of the extracellular matrix and the vascular network. Additionally, during efferocytosis, phagocytic cells produce a number of anti-inflammatory and resolving factors, and, together with apoptotic cells, efferocytic events have a homeostatic function that regulates tissue repair. These homeostatic functions are dysregulated in cancers, where, aforementioned events, if not properly controlled, can lead to cancer progression and immune escape. Here, we summarize evidence that apoptosis and efferocytosis are exploited in cancer, as well as discuss current translation and clinical efforts to harness signals from dying cells into therapeutic strategies.

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The clearance of dead cells by efferocytosis

Cited by 514 publications

References 256 publications

Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis

Omega-3 Docosahexaenoic Acid (DHA) Impedes Silica-Induced Macrophage Corpse Accumulation by Attenuating Cell Death and Potentiating Efferocytosis

Loss of CIB2 causes non-canonical autophagy deficits and visual impairment

Cell Death in the Tumor Microenvironment: Implications for Cancer Immunotherapy

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