Previous Uptake of Apoptotic Neutrophils or Ligation of Integrin Receptors Downmodulates the Ability of Macrophages to Ingest Apoptotic Neutrophils

• Published in: Blood 1999-02, Vol.93 (4), p.1406-1412
• Main Authors: Erwig, Lars-Peter, Gordon, Sharon, Walsh, Garry M., Rees, Andrew J.
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Biological and medical sciences; Cell Communication; Cell physiology; Cells, Cultured; Coculture Techniques; Cytokines - pharmacology; Endocytosis; Fundamental and applied biological sciences. Psychology; Humans; Ligands; Macrophage Activation; Macrophages - metabolism; Macrophages - pathology; Molecular and cellular biology; Neutrophil Activation; Neutrophils - metabolism; Neutrophils - pathology; Phagocytosis; Rats; Receptors, Vitronectin - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V93.4.1406

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)-γ, interleukin (IL)-4, and IL-10. It was inhibitable by the tetrapeptide arg-gly-gln-ser (RGDS), therefore implicating the αvβ3/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 αvβ3 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 α6β1 and α1β2, 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.