Phagocytosis of apoptotic neutrophils does not induce macrophage release of thromboxane B2

Abstract

Senescent human neutrophils undergo programmed cell death (apoptosis), leading to their recognition and phagocytosis by mature macrophages. At inflamed sites in vivo these processes may represent a neutrophil removal mechanism with the potential to limit the histotoxic capacity of these cells. Phagocytosis can provoke marked proinflammatory responses by macrophages. A macrophage proinflammatory response to the ingestion of apoptotic neutrophils would limit the efficacy of this neutrophil removal mechanism as a component of inflammatory resolution. In the present study we examined two macrophage proinflammatory responses; secretion of the granule enzyme N-acetyl-beta-D-glucosaminidase (NAG) and release of the membrane lipid-derived inflammatory mediator thromboxane A2 (TxA2, measured as TxB2). By contrast with the marked release of NAG and TxB2 elicited by phagocytosis of control particles (opsonised zymosan and immunoglobulin G-coated erythrocytes), macrophage ingestion of apoptotic neutrophils resulted in minimal release of NAG and no release of TxB2; indeed, there was a small depression of TxB2 release that was not due to a toxic effect of neutrophil uptake because macrophages ingesting apoptotic neutrophils retained marked TxB2 responses to subsequent stimulation with opsonised zymosan. Furthermore, there was significant TxB2 release in response to macrophage phagocytosis of apoptotic neutrophils that had been coated with opsonic serum, demonstrating that the lack of macrophage response was determined by the mechanism of recognition rather than the properties of the apoptotic particle itself. These observations are consistent with the hypothesis that macrophage clearance of senscent neutrophils undergoing apoptosis is an injury-limiting mechanism that favors resolution rather than persistence of the inflammatory response and are consistent with observations that the waves of apoptotic cell removal seen in embryological removal and thymic involution do not trigger an inflammatory response.

Safe disposal of inflammatory monosodium urate monohydrate crystals by differentiated macrophages

“…Another relevant observation from the apoptotic neutrophil field is that the normal noninflammatory clearance mechanisms of macrophages can be subverted by concomitant engagement of Fc receptors (32). Coating of MSU crystals with IgG may thus predispose certain individuals to a more proinflammatory reaction to crystal deposition in their joints.…”

On the influence of neutrophils in corneas with necrotizing HSV-1 keratitis following amniotic membrane transplantation

“…We noted that AMT covered mouse corneas show rapid resolution of corneal inflammation consistent with rapid reduction of PMN (Heiligenhaus et al, 2001). Previously, it has been suggested that apoptosis of PMN is a new strategy to clear a large number of PMN and their potentially histotoxic contents to achieve rapid resolution of acute inflammation (Meagher et al, 1992;Stern et al, 1996). Therefore, we re-examined this mouse model of HSK-induced necrotizing keratitis and investigated the mechanism explaining the fate of PMN after AMT.…”

Hypoxia prolongs neutrophil survival in vitro

“…When neutrophils die by apoptosis they retain their granule contents but lose chemotactic and secretory responsiveness [8] and thereafter are recognised and phagocytosed intact by macrophages [9] which fail to release pro-inflammatory mediators in response to this interaction [10]. Although neutrophils un-*Corresponding author.…”