Nonphlogistic Clearance of Late Apoptotic Neutrophils by Macrophages: Efficient Phagocytosis Independent of β2 Integrins

Ren, Yi; Stuart, Lynda M.; Lindberg, Frederik P.; Rosenkranz, Alexander R.; Chen, Yongmei; Mayadas, Tanya N.; Savill, John

doi:10.4049/jimmunol.166.7.4743

Cited by 94 publications

(75 citation statements)

References 44 publications

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“…7). These results are in keeping with the earlier observations of Ren and Savill, who observed that apoptotic neutrophils beginning to become permeable to trypan blue were not proinflammatory (14). The response to lysed cells in the unstimulated macrophages was expected (2) in that they induced TNF-␣ and chemokine production; however, the levels were low relative to those seen with a strong proinflammatory stimulus such as zymosan or LPS (the latter not shown).…”

Section: Discussionsupporting

confidence: 76%

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

Fadok

Bratton

Guthrie

et al. 2001

The Journal of Immunology

338

284

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Granulocytes undergoing apoptosis are recognized and removed by phagocytes before their lysis. The release of their formidable arsenal of proteases and other toxic intracellular contents into tissues can create significant damage, prolonging the inflammatory response. Binding and/or uptake of apoptotic cells by macrophages inhibits release of proinflammatory cytokines by mechanisms that involve anti-inflammatory mediators, including TGF-β. To model the direct effects of necrotic cells on macrophage cytokine production, we added lysed or apoptotic neutrophils and lymphocytes to mouse and human macrophages in the absence of serum to avoid complement activation. The results confirmed the ability of lysed neutrophils, but not lymphocytes, to significantly stimulate production of macrophage-inflammatory protein 2 or IL-8, TNF-α, and IL-10. Concomitantly, induction of TGF-β1 by lysed neutrophils was significantly lower than that observed for apoptotic cells. The addition of selected serine protease inhibitors and anti-human elastase Ab markedly reduced the proinflammatory effects, the lysed neutrophils then behaving as an anti-inflammatory stimulus similar to intact apoptotic cells. Separation of lysed neutrophils into membrane and soluble fractions showed that the neutrophil membranes behaved like apoptotic cells. Thus, the cytokine response seen when macrophages were exposed to lysed neutrophils was largely due to liberated proteases. Therefore, we suggest that anti-inflammatory signals can be given by PtdSer-containing cell membranes, whether from early apoptotic, late apoptotic, or lysed cells, but can be overcome by proteases liberated during lysis. Therefore, the outcome of an inflammatory reaction and the potential immunogenicity of Ags within the damaged cell will be determined by which signals predominate.

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Section: Discussionsupporting

confidence: 76%

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

Fadok

Bratton

Guthrie

et al. 2001

The Journal of Immunology

338

284

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“…Phagocytosis of apoptotic neutrophils induced macrophages to secrete antiinflammatory cytokines and actively inhibited the production of proinflammatory cytokines (46). Similarly, late apoptotic neutrophils ingested by macrophages did not trigger the release of proinflammatory cytokines (47), whereas necrotic neutrophils induced macrophages to secrete inflammation mediators (48) and were able to efficiently costimulate T cells due to rapid up-regulation of CD40 (49). Clearly, these results and the results of the current study emphasize the differential effects of apoptotic and necrotic cells on macrophages and DCs and highlight the need for study of other types of primary cells.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Clayton¹,

Prue²,

Harper³

et al. 2003

Arthritis & Rheumatism

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Objective. There is a breakdown of tolerance to neutrophil components during systemic vasculitis, which is marked by autoantibodies and T cells with specificity for proteinase 3 or myeloperoxidase, expressed on the surface of apoptotic neutrophils. This study was undertaken to investigate the effects of human apoptotic and necrotic neutrophils on human dendritic cell (DC) phenotype and ability to stimulate allogeneic T cell proliferation.Methods. DCs were generated from human peripheral blood mononuclear cells and allowed to interact with human apoptotic and necrotic neutrophils in the presence or absence of tumor necrosis factor ␣ (TNF␣). Effects on DC phenotype and ability to stimulate T cell proliferation were observed.Results. Immature DCs engulfed apoptotic and necrotic neutrophils, resulting in up-regulation of CD83 and class II major histocompatibility complex molecules, but down-regulation of CD40, CD80, and CD86, and a decreased ability to stimulate T cell proliferation. When TNF␣ was added in combination with apoptotic neutrophils, the inhibitory effects were overcome to some extent.Conclusion. Our results suggest that DC uptake of apoptotic or necrotic neutrophils alone does not shift the immune response from tolerance to autoimmunity in systemic vasculitis. However, cytokines found at sites of inflammation in vasculitis patients may act as maturation factors for DCs, and in combination with apoptotic neutrophils, may lead to an autoimmune phenotype.

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“…25 Briefly, neutrophil suspensions were added to discontinuous Percoll gradients created by gently layering equal volumes of 31, 42 and 51% of a standard isotonic Percoll solution (90% Percoll þ 10% 10 Â phosphate-buffered saline (PBS)) in diluent (PBS) and centrifuged at 610 g for 28 min at 41C. The 0/31 and 42/51% Percoll interfaces contained the majority of necrotic, late and early apoptotic cells (490% were annexin-V-positive cells or incorporated PI), whereas the viable cells were collected at the bottom.…”

Section: Preparation Of Human Leukocytesmentioning

confidence: 99%

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

Chakravarti

Rusu

Flamand

et al. 2009

Laboratory Investigation

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Essential cells of innate immunity, neutrophils are often considered to be a homogenous population of terminally differentiated cells. During inflammation, neutrophils are extravasated cells exposed to local factors that prolong their survival and activate their production of mediators implicated in disease progression. In this study, a phenotypically distinct subset of human neutrophils that appear after prolonged exposure to cytokines was characterized. Freshly isolated neutrophils from healthy donors were incubated with granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-a and interleukin (IL)-4, three cytokines that are locally present in various inflammatory conditions. Eight to 17% of neutrophils survived beyond 72 h. This subset of non-apoptotic neutrophils, as evaluated by three different markers, was enriched by discontinuous Percoll gradient centrifugation before studying their phenotype. These viable neutrophils showed neoexpression of HLA-DR, CD80 and CD49d. Compared with freshly isolated neutrophils, they responded differentially to second signals similar to formyl-methionyl-leucyl-phenylalanine with three-to four-fold increases in production of superoxide anions and leukotrienes. These cells augmented their phagocytic index by 141%, increased their adhesion to human primary fibroblasts, but reduced their migration in response to chemotactic stimuli and decreased exocytosis of primary and secondary granules. In addition, they produced substantial amounts of IL-8, IL-1Ra and IL-1b. This neutrophil subset had a unique profile of phosphorylation of intracellular signaling molecules. In conclusion, the present identification of a novel neutrophil phenotype highlights the reprogammable character of the neutrophil. This aspect is crucial for our understanding of its contribution to disease pathogenesis and host defense.

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Nonphlogistic Clearance of Late Apoptotic Neutrophils by Macrophages: Efficient Phagocytosis Independent of β2 Integrins

Cited by 94 publications

References 44 publications

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

Differential Effects of Apoptotic Versus Lysed Cells on Macrophage Production of Cytokines: Role of Proteases

Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

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