Previous uptake of apoptotic neutrophils or ligation of integrin receptors downmodulates the ability of macrophages to ingest apoptotic neutrophils

L P Erwig, S Gordon, G M Walsh, A J Rees

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

Clearance of apoptotic neutrophils (polymorphonuclear leukocyte [PMN]) by macrophages is thought to play a crucial role in resolution of acute inflammation. There is increasing evidence that ingestion of apoptotic cells modulates macrophage behavior. We therefore performed experiments to determine whether ingestion of apoptotic PMN modulated the uptake process itself. Rat bone marrow-derived macrophages (BMDM) ingested apoptotic PMN by a process that was enhanced by tumor necrosis factor (TNF) and attenuated by interferon (IFN)-gamma, interleukin (IL)-4, and IL-10. it was inhibitable by the tetrapeptide arg-gly-gln-ser (RGDS), therefore implicating the alpha v beta 3/CD36/thrombospondin pathway. Interaction of apoptotic PMN with BMDM for 30 minutes, 48 hours before rechallenge reduced uptake of apoptotic PMN by 50% compared with previously unchallenged BMDM. Blocking initial uptake with RGDS abrogated the effect of preexposure. Comparable and sustained attenuation of uptake was obtained by ligating alpha v beta 3 with the monoclonal antibody (MoAb), F11, after a delay of more than 90 minutes, whereas MoAbs to CD25 and CD45 had no effect. Ligation of alpha 6 beta 1 and alpha 1 beta 2, integrins not previously implicated in the engulfment of apoptotic cells also decreased uptake with similar kinetics to F11. Therefore, apoptotic PMN regulate their own uptake through an integrin-dependent process, which can be reproduced by ligation of other Integrins expressed by macrophages. (C) 1999 by The American Society of Hematology.

Original languageEnglish
Pages (from-to)1406-1412
Number of pages7
JournalBlood
Volume93
Publication statusPublished - 1999

Keywords

  • PROGRAMMED CELL-DEATH
  • VITRONECTIN RECEPTOR
  • INFLAMMATORY MACROPHAGES
  • RECOGNITION MECHANISM
  • MEDIATED PHAGOCYTOSIS
  • RAT OSTEOCLASTS
  • PHOSPHATIDYLSERINE
  • LYMPHOCYTES
  • RESOLUTION
  • SURFACE

Cite this

Previous uptake of apoptotic neutrophils or ligation of integrin receptors downmodulates the ability of macrophages to ingest apoptotic neutrophils. / Erwig, L P ; Gordon, S ; Walsh, G M ; Rees, A J .

In: Blood, Vol. 93, 1999, p. 1406-1412.

Research output: Contribution to journalArticle

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N2 - Clearance of apoptotic neutrophils (polymorphonuclear leukocyte [PMN]) by macrophages is thought to play a crucial role in resolution of acute inflammation. There is increasing evidence that ingestion of apoptotic cells modulates macrophage behavior. We therefore performed experiments to determine whether ingestion of apoptotic PMN modulated the uptake process itself. Rat bone marrow-derived macrophages (BMDM) ingested apoptotic PMN by a process that was enhanced by tumor necrosis factor (TNF) and attenuated by interferon (IFN)-gamma, interleukin (IL)-4, and IL-10. it was inhibitable by the tetrapeptide arg-gly-gln-ser (RGDS), therefore implicating the alpha v beta 3/CD36/thrombospondin pathway. Interaction of apoptotic PMN with BMDM for 30 minutes, 48 hours before rechallenge reduced uptake of apoptotic PMN by 50% compared with previously unchallenged BMDM. Blocking initial uptake with RGDS abrogated the effect of preexposure. Comparable and sustained attenuation of uptake was obtained by ligating alpha v beta 3 with the monoclonal antibody (MoAb), F11, after a delay of more than 90 minutes, whereas MoAbs to CD25 and CD45 had no effect. Ligation of alpha 6 beta 1 and alpha 1 beta 2, integrins not previously implicated in the engulfment of apoptotic cells also decreased uptake with similar kinetics to F11. Therefore, apoptotic PMN regulate their own uptake through an integrin-dependent process, which can be reproduced by ligation of other Integrins expressed by macrophages. (C) 1999 by The American Society of Hematology.

AB - Clearance of apoptotic neutrophils (polymorphonuclear leukocyte [PMN]) by macrophages is thought to play a crucial role in resolution of acute inflammation. There is increasing evidence that ingestion of apoptotic cells modulates macrophage behavior. We therefore performed experiments to determine whether ingestion of apoptotic PMN modulated the uptake process itself. Rat bone marrow-derived macrophages (BMDM) ingested apoptotic PMN by a process that was enhanced by tumor necrosis factor (TNF) and attenuated by interferon (IFN)-gamma, interleukin (IL)-4, and IL-10. it was inhibitable by the tetrapeptide arg-gly-gln-ser (RGDS), therefore implicating the alpha v beta 3/CD36/thrombospondin pathway. Interaction of apoptotic PMN with BMDM for 30 minutes, 48 hours before rechallenge reduced uptake of apoptotic PMN by 50% compared with previously unchallenged BMDM. Blocking initial uptake with RGDS abrogated the effect of preexposure. Comparable and sustained attenuation of uptake was obtained by ligating alpha v beta 3 with the monoclonal antibody (MoAb), F11, after a delay of more than 90 minutes, whereas MoAbs to CD25 and CD45 had no effect. Ligation of alpha 6 beta 1 and alpha 1 beta 2, integrins not previously implicated in the engulfment of apoptotic cells also decreased uptake with similar kinetics to F11. Therefore, apoptotic PMN regulate their own uptake through an integrin-dependent process, which can be reproduced by ligation of other Integrins expressed by macrophages. (C) 1999 by The American Society of Hematology.

KW - PROGRAMMED CELL-DEATH

KW - VITRONECTIN RECEPTOR

KW - INFLAMMATORY MACROPHAGES

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KW - RAT OSTEOCLASTS

KW - PHOSPHATIDYLSERINE

KW - LYMPHOCYTES

KW - RESOLUTION

KW - SURFACE

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