Having an Old Friend for Dinner: The Interplay between Apoptotic Cells and Efferocytes

Lam, Austin Le; Heit, Bryan

doi:10.3390/cells10051265

Cited by 11 publications

(5 citation statements)

References 253 publications

(366 reference statements)

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“…By addressing the role of TAM receptors, we found that both Axl and Mer promote BMDM-mediated efferocytosis of proapoptotic T cells from T. cruzi-infected mice. Although the sources of macrophages and apoptotic T cells are distinct in this and the previous experimental model, it is conceivable that a few or multiple receptors, such as αvβ3, Axl, Mer, and other putative receptors, such as TIM4 41 , work in concert in efferocytosis, as previously suggested [42][43][44] . Moreover, upon binding to apoptotic cell ligands, receptors might cluster together in an efferocytosisinduced molecular platform dedicated to tethering, phagocytosis, and inhibitory signalling response to apoptotic cells.…”

Section: Discussionmentioning

confidence: 53%

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

et al. 2022

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Adaptive immunity controls Trypanosoma cruzi infection, but the protozoan parasite persists and causes Chagas disease. T cells undergo apoptosis, and the efferocytosis of apoptotic cells might suppress macrophages and exacerbate parasite infection. Nonetheless, the receptors involved in the efferocytosis of apoptotic lymphocytes during infection remain unknow. Macrophages phagocytose apoptotic cells by using the TAM (Tyro3, Axl, Mer) family of receptors. To address how the efferocytosis of apoptotic cells affects macrophage-mediated immunity, we employ here Axl receptor- and Mer receptor-deficient mouse strains. In bone marrow-derived macrophages (BMDMs), both Axl and Mer receptors play a role in the efferocytosis of proapoptotic T cells from T. cruzi-infected mice. Moreover, treatment with a TAM receptor inhibitor blocks efferocytosis and upregulates M1 hallmarks induced by immune T cells from infected mice. Remarkably, the use of Axl−/− but not Mer−/− macrophages increases T-cell-induced M1 responses, such as nitric oxide production and control of parasite infection. Furthermore, infected Axl−/− mice show reduced peak parasitemia, defective efferocytosis, improved M1 responses, and ameliorated cardiac inflammation and fibrosis. Therefore, Axl induces efferocytosis, disrupts M1 responses, and promotes parasite infection and pathology in experimental Chagas disease. Axl stands as a potential host-direct target for switching macrophage phenotypes in infectious diseases.

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Section: Discussionmentioning

confidence: 53%

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

et al. 2022

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“…This process of clearing apoptotic cells is called efferocytosis. The efferocytosis process is divided into three stages: recognition, binding, and cell death degradation [ 12 , 13 ]. Various markers of each stage have been identified.…”

Section: Introductionmentioning

confidence: 99%

The Important Role of Phosphatidylserine, ADAM17, TNF-Alpha, and Soluble MER on Efferocytosis Activity in Central Obesity

Purnama,

Meiliana,

Barliana

et al. 2024

Journal of Obesity

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Background. Obesity is expected to hinder efferocytosis due to ADAM17-mediated cleavage of the MER tyrosine kinase receptor, producing soluble MER (sMER) that disrupts MERTK binding to cell death markers. However, the intracellular efferocytosis pathway in central obesity remains elusive, particularly the role of low-grade chronic inflammation in its initiation and identification of binding signals that disrupt efferocytosis. Objective. We investigate the efferocytosis signaling pathway in men with central obesity and its relationship with inflammation, cell death, and related processes. Methods. A cross-sectional study was conducted, and clinical data and blood samples were collected from 56 men with central obesity (obese group) and 29 nonobese individuals (control group). Clinical evaluations and predefined biochemical screening tests were performed. The efferocytosis signaling pathway was investigated by measuring phosphatidylserine (PS), ADAM17, TNF-alpha (TNF-α), and sMER. Results. Metabolic syndrome was detected in more than half of the participants in the obese group according to the predefined tests. Mean levels of PS, TNF-α, and sMER were higher in the obese group but not significantly different from those of the control group. Further analysis based on waist circumference (WC) ranges in the obese group revealed a significant increase in PS and sMER levels between the control group and the obese group with WC greater than 120 cm. ADAM17 levels were significantly higher in the obese group than in the control group. PS was positively correlated with WC and ADAM17. ADAM17 was positively correlated with TNF-α and sMER, indicating impaired efferocytosis. Conclusions. Central obesity appeared to cause a disturbance in efferocytosis that began with cell damage and death, along with an enlargement of the WC and an ongoing inflammatory response. Efferocytosis was disrupted by proinflammatory cytokine regulators, which induced the production of sMER and interfered with the efferocytosis process.

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“…This is due to the ability of phagocytosis to prevent secondary necrosis of apoptotic cells and the release of autoantigens and proinflammatory alarmins (7). These antiinflammatory effects are particularly important at mucosal locations such as the lung where the epithelium can turn over every 7-21 days (7)(8)(9)(10)(11)(12)(13). Efferocytosis is an evolutionarily conserved, highly regulated, multistep process that includes mononuclear cell recognition of apoptotic cells and the proper interpretation of the signals they send (7).…”

Section: Introductionmentioning

confidence: 99%

Chitinase 3-like-1 (CHI3L1) Inhibits Innate Anti-Tumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα and CD24-Siglec10-Mediated Phagocytosis

Ma,

Kamle,

Lee

et al. 2023

Preprint

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Innate immune responses such as phagocytosis are critically linked to the generation of adaptive immune responses against the neoantigens in cancer and the efferocytosis that is essential for homeostasis in diseases characterized by lung injury, inflammation, and remodeling as in Chronic Obstructive Pulmonary Disease (COPD). Chitinase 3-like-1 (CHI3L1) is induced in many cancers where it inhibits adaptive immune responses by stimulating immune checkpoint molecules (ICPs) and portends a poor prognosis. CHI3L1 is also induced in COPD where it regulates epithelial cell death. Here we demonstrate that pulmonary melanoma metastasis inhibits macrophage phagocytosis by stimulating the CD47-SIRPα and CD24-Siglec10 phagocytosis checkpoint pathways while inhibiting macrophage “eat me” signals from calreticulin and HMGB1. We also demonstrate that these effects on macrophage phagocytosis are mediated by CHI3L1 stimulation of the SHP-1 and SHP-2 phosphatases and the inhibition of the accumulation and phosphorylation of cytoskeleton-regulating non-muscle myosin IIa. This inhibition of innate immune responses like phagocytosis provides a mechanistic explanation for the ability of CHI3L1 to stimulate ICPs and inhibit adaptive immune responses in cancer and diseases like COPD. The ability of CHI3L1 to simultaneously inhibit innate immune responses, stimulate ICPs, inhibit T cell co-stimulation, and regulate a number of other oncogenic and inflammation pathways suggest that CHI3L1-targeted therapeutics are promising interventions in cancer, COPD and other disorders.

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Having an Old Friend for Dinner: The Interplay between Apoptotic Cells and Efferocytes

Cited by 11 publications

References 253 publications

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

Axl receptor induces efferocytosis, dampens M1 macrophage responses and promotes heart pathology in Trypanosoma cruzi infection

The Important Role of Phosphatidylserine, ADAM17, TNF-Alpha, and Soluble MER on Efferocytosis Activity in Central Obesity

Chitinase 3-like-1 (CHI3L1) Inhibits Innate Anti-Tumor and Tissue Remodeling Immune Responses by Regulating CD47-SIRPα and CD24-Siglec10-Mediated Phagocytosis

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