Phagocytosis of apoptotic cells by human macrophages: Analysis by multiparameter flow cytometry

Jersmann, Hubertus; Ross, Karen; Vivers, Sharon; Brown, Simon; Haslett, Christopher; Dransfield, Ian

doi:10.1002/cyto.a.10005

Cited by 57 publications

(57 citation statements)

References 26 publications

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“…Recent data indicate that normal scavenging mechanisms that clear apoptotic cells can inhibit acute inflammatory responses (34)(35)(36). Macrophages ingesting apoptotic cells release IL-10, a regulatory cytokine that suppresses Th2 inflammation and inhibits tumor necrosis factor α production (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines

et al. 2004

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The mechanisms that initiate allergic lung inflammation are relevant to expression of diseases such as asthma, but the factors underlying resolution of inflammation are equally important. Previously, we demonstrated the importance of matrix metalloproteinase 2 (MMP2) for airway egression of lung eosinophils, a critical anti-inflammatory mechanism without which mice are rendered highly susceptible to lethal asphyxiation. Here we show that leukocyte MMP9 is the dominant airway MMP controlling inflammatory cell egression. The allergic lung phenotype of MMP9 −/− mice was similar to WT and was not altered by concomitant deletion of the MMP2 gene (double knockout; dko). However, inflammatory cells accumulated aberrantly in the lungs of allergen-challenged MMP9 −/− and dko mice and fewer eosinophils and neutrophils were present in bronchoalveolar lavage. These aberrant cellular trafficking patterns were explained by disruption of transepithelial chemokine gradients, in MMP2 −/− mice affecting only eotaxin (CCL11), but in MMP9 −/− and dko mice involving eotaxin, MARC (CCL7), and TARC (CCL17). Thus, by establishing multiple transepithelial chemokine gradients, MMP9 is broadly implicated in the resolution of allergic inflammation, an essential protective mechanism that overlaps with a more limited role played by MMP2.

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Section: Discussionmentioning

confidence: 99%

Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines

et al. 2004

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“…Phagocytosis of apoptotic cells was assessed essentially as described (30), using a method that has been carefully characterized and shown to discriminate between bound and internalized apoptotic cells, comparing favorably with microscopy analysis. CMFDA-labeled apoptotic neutrophils were centrifuged at 200 ϫ g and resuspended at 2.5 ϫ 10 6 /ml in IMDM, and 0.5 ml was overlaid onto MDM that had been cultured in 48-well plates (ϳ200,000 MDM/well, a ratio of ϳ10 neutrophils per macrophage) and then coincubated for 30 min at 37°C in 5% CO 2 .…”

Section: Apoptotic Cell Phagocytosis Assaymentioning

confidence: 99%

Glucocorticoids Induce Protein S-Dependent Phagocytosis of Apoptotic Neutrophils by Human Macrophages

McColl

Bournazos

Franz

et al. 2009

The Journal of Immunology

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116

119

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During resolution of an inflammatory response, recruited neutrophil granulocytes undergo apoptosis and are removed by tissue phagocytes before induction of secondary necrosis without provoking proinflammatory cytokine production and release. Promotion of physiological neutrophil clearance mechanisms may represent a viable therapeutic strategy for the treatment of inflammatory or autoimmune diseases in which removal of apoptotic cells is impaired. The mechanism underlying enhancement of macrophage capacity for phagocytosis of apoptotic cells by the powerful anti-inflammatory drugs of the glucocorticoid family has remained elusive. In this study, we report that human monocyte-derived macrophages cultured in the presence of dexamethasone exhibit augmented capacity for phagocytosis of membrane-intact, early apoptotic cells only in the presence of a serum factor. Our results eliminate a role for a number of potential opsonins, including complement, pentraxin-3, and fibronectin. Using ion-exchange and gel filtration chromatography, we identified a high molecular mass serum fraction containing C4-binding protein and protein S responsible for the augmentation of phagocytosis of apoptotic neutrophils. Because the apoptotic neutrophils used in this study specifically bind protein S, we suggest that glucocorticoid treatment of macrophages induces a switch to a protein S-dependent apoptotic cell recognition mechanism. Consistent with this suggestion, pretreatment of macrophages with Abs to Mer tyrosine kinase, a member of the Tyro3/Axl/Mer family of receptor tyrosine kinases, prevented glucocorticoid augmentation of phagocytosis. Induction of a protein S/Mer tyrosine kinase-dependent apoptotic cell clearance pathway may contribute to the potent anti-inflammatory effects of glucocorticoids, representing a potential target for promoting resolution of inflammatory responses.

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“…THP-1 phagocytosis of apoptotic leukocytes was assessed using a flow cytometric assay as previously described (19). THP-1 cells (1 ϫ 10 6 cells/ ml) were differentiated to a macrophage-like phenotype by treatment with PMA (10 nM, 48 h) in 24-well plates (Costar).…”

Section: Phagocytosis Of Apoptotic Leukocytesmentioning

confidence: 99%

Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes

Reville

Crean

Vivers

et al. 2006

The Journal of Immunology

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Lipoxins (LXs) are endogenously produced anti-inflammatory agents that modulate leukocyte trafficking and stimulate nonphlogistic macrophage phagocytosis of apoptotic neutrophils, thereby promoting the resolution of inflammation. Previous data suggest a role for altered protein phosphorylation and cytoskeletal rearrangement in LX-stimulated phagocytosis but the exact mechanisms remain unclear. In this study we examine the effects of LXA4 on the protein phosphorylation pattern of THP-1 cells differentiated into a macrophage-like phenotype. THP-1 cells stimulated with LXA4 (1 nM) exhibit dephosphorylation of a 220-kDa protein. Using mass spectrometry, this protein was identified as MYH9, a nonmuscle myosin H chain II isoform A, which is involved in cytoskeleton rearrangement. THP-1 cells treated with LXA4 adopt a polarized morphology with activated Cdc42 localized toward the leading edge and MYH9 localized at the cell posterior. Polarized distribution of Cdc42 is associated with Akt/PKB-mediated Cdc42 activation. Interestingly, the annexin-derived peptide Ac2–26, a recently described agonist for the LXA4 receptor, also stimulates macrophage phagocytosis, MYH9 dephosphorylation, and MYH9 redistribution. In addition, we demonstrate that LXA4 stimulates the phosphorylation of key polarity organization molecules: Akt, protein kinase Cζ, and glycogen synthase kinase-3β. Inhibition of LXA4-induced Akt and protein kinase Cζ activity with specific inhibitors prevented LXA4-stimulated phagocytosis of both apoptotic polymorphonuclear neutrophils and lymphocytes, highlighting a potential use for LXA4 in the treatment of autoimmune diseases. Furthermore, phosphorylation and subsequent inactivation of glycogen synthase kinase-3β resulted in an increase in phagocytosis similar to that of LXA4. These data highlight an integrated mechanism whereby LXA4 regulates phagocytosis through facilitative actin cytoskeleton rearrangement and cell polarization.

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Phagocytosis of apoptotic cells by human macrophages: Analysis by multiparameter flow cytometry

Cited by 57 publications

References 26 publications

Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines

Overlapping and independent contributions of MMP2 and MMP9 to lung allergic inflammatory cell egression through decreased CC chemokines

Glucocorticoids Induce Protein S-Dependent Phagocytosis of Apoptotic Neutrophils by Human Macrophages

Lipoxin A4 Redistributes Myosin IIA and Cdc42 in Macrophages: Implications for Phagocytosis of Apoptotic Leukocytes

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