Neutrophils Accelerate Macrophage-Mediated Digestion of Apoptotic Cells In Vivo as Well as In Vitro

Iyoda, Takuya; Nagata, Kisaburo; Akashi, Makoto; Kobayashi, Yoshiro

doi:10.4049/jimmunol.175.6.3475

Cited by 30 publications

(20 citation statements)

References 70 publications

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“…In another study MF-mediated digestion of apoptotic thymocytes was accelerated in the presence of neutrophils both in vivo and in vitro suggesting that recruitment of neutrophils to the site of massive apoptosis does not induce inflammation but rather accelerates complete digestion of apoptotic cells (48). In light of our results, neutrophils likely contribute to the disappearance of apoptotic cells by participating actively in the clearance of apoptotic cells.…”

Section: Discussionsupporting

confidence: 60%

Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes: Diminished Proinflammatory Neutrophil Functions in the Presence of Apoptotic Cells

Esmann

Idel

Sarkar

et al. 2009

The Journal of Immunology

102

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Neutrophil granulocytes are rapidly recruited from the bloodstream to the site of acute inflammation where they die in large numbers. Because release of toxic substances from dead neutrophils can propagate the inflammatory response leading to tissue destruction, clearance of dying inflammatory neutrophils has a critical function in the resolution of the inflammatory response. Apoptotic neutrophils are phagocytosed primarily by macrophages, provided these cells are present in adequate numbers. However, macrophages are rare at sites of acute inflammation, whereas the number of neutrophils can be extremely high. In the current study, in vitro experiments with human neutrophils were carried out to investigate whether neutrophils can ingest apoptotic neutrophils. We show that naïve granulocytes isolated from venous blood have a limited capacity to phagocytose apoptotic cells. However, exposure to activating stimuli such as LPS, GM-CSF and/or IFN-γ results in enhanced phagocytosis of apoptotic cells. The efficient uptake of apoptotic cells by neutrophils was found to depend on the presence of heat labile serum factors. Importantly, the contact to or uptake of apoptotic cells inhibited neutrophil functions such as respiratory burst and the release of the proinflammatory cytokines TNF-α and interferon-inducible protein-10. Contact to apoptotic cells, however, induced the secretion of IL-8 and growth-related oncogene-α, which was independent of NF-κB and p38 MAPK but involved C5a and the ERK1/2 pathway. The data suggest that activated neutrophils participate in the clearance of apoptotic cells. In addition, because apoptotic cells inhibit proinflammatory functions of neutrophils, uptake of apoptotic cells by neutrophils contributes to the resolution of inflammation.

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Section: Discussionsupporting

confidence: 60%

Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes: Diminished Proinflammatory Neutrophil Functions in the Presence of Apoptotic Cells

Esmann

Idel

Sarkar

et al. 2009

The Journal of Immunology

102

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“…This observation is further evidence that dietary antioxidants likely attenuate the radiation-induced inflammatory state, which results in neutrophil demarginalization (33). For instance, in the thymus, neutrophils are recruited from the periphery after massive TBI-induced lymphoid apoptosis and prior to clearance of the apoptotic cells by macrophages (34,35). Such apoptotic tissue injury initiates an immune response that leads to neutrophil demarginalization and peripheral neutrophilia prior to tissue infiltration.…”

Section: Discussionmentioning

confidence: 76%

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

et al. 2008

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The purpose of this study was to determine whether a dietary supplement consisting of Lselenomethionine, vitamin C, vitamin E succinate, α-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-β1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.

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“…Because the majority of developing thymocytes will fail positive or negative selection, scavenger cells such as macrophages play an important role in thymopoiesis. 42,43 A recent study showed that mice deficient for neutrophil migration were impaired in their ability to clear apoptotic cells after irradiation. 44 Therefore, it is possible that granulocytes function as scavengers of apoptotic thymocytes in the steady state.…”

Section: Discussionmentioning

confidence: 99%

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

Obaldia

Bell

Bhandoola

2013

Blood

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Key Points• Granulocytes in the adult mouse thymus share a common origin with T cells, because they derive from ETPs.• The finding that ETPs generate myeloid cells in vivo indicates that precursors settling the thymus include myelolymphoid progenitors. IntroductionSince the identification of early T-lineage precursors (ETPs), 1 much work has characterized the developmental potentials possessed by this population. [2][3][4][5][6][7][8][9][10][11][12][13] In addition to robust T-cell developmental potential, ETPs have been shown to possess B cell, dendritic cell (DC), and natural killer (NK) cell potential and a degree of myeloid potential. As ETPs progress along the T-cell developmental pathway, they gradually lose non-T-cell potentials and generate CD4/ CD8-double negative 2 (DN2) progenitors and, finally, DN3 cells that are committed to the T-cell lineage. Single-cell assays using a stromal cell culture system have shown that the majority of individual ETPs can give rise to both T cells and myeloid cells, including granulocytes and macrophages. 10,11 However, less is known about the extent to which ETPs realize this myeloid potential and other non-T-cell lineage potentials in vivo. We reported previously that approximately half of ETPs and a similar fraction of thymic granulocytes were labeled in H2-VEX V(D)J recombination reporter mice. 10 These data are consistent with the notion that thymic granulocytes share a common origin with T cells. Since then, another study examining thymic myeloid cells using an IL-7 receptor (IL-7R)/Cre lineage tracing approach yielded discordant results. 12 Therefore, further examination was needed to determine whether ETPs can produce granulocytes in vivo and whether ETPs are the major precursors of thymic granulocytes. An understanding of whether ETPs generate both myeloid and T-cell progeny in vivo will contribute to a more complete model of hematopoietic development.In the present study, we examined thymic granulocyte development in experimental contexts in which ETPs are nearly absent. We reasoned that non-T-lineage cells in the thymus that are unperturbed in the absence of ETPs in mixed-BM chimeras must not predominantly derive from ETPs. Previous studies used a similar approach to investigate whether non-T-lineage cells in the thymus originate from T-cell progenitors; however, these studies did not examine thymic granulocytes. 14,15 Studies using models that exclusively block intrathymic ETP development (eg, by ablating Notch signaling) may fail to detect a common origin with T-cell progenitors because progenitors continue to settle the thymus and may still generate non-T-lineage cells even when ETP development is abrogated. To address this concern, we chose to study the development of non-T-lineage cells in the thymus by eliminating T-cell progenitors before thymic entry. Specifically, we examined mixed chimeras using CCR7/CCR9 double-deficient donor BM in which T-cell progenitors display defective thymic settling and thus generate almost no ETPs. In addition, we examined ...

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Neutrophils Accelerate Macrophage-Mediated Digestion of Apoptotic Cells In Vivo as Well as In Vitro

Cited by 30 publications

References 70 publications

Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes: Diminished Proinflammatory Neutrophil Functions in the Presence of Apoptotic Cells

Phagocytosis of Apoptotic Cells by Neutrophil Granulocytes: Diminished Proinflammatory Neutrophil Functions in the Presence of Apoptotic Cells

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

Early T-cell progenitors are the major granulocyte precursors in the adult mouse thymus

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