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Abstract
Physiologically the only acceptable fate for almost all damaged or unwanted cells
is their apoptotic death, followed by engulfment of the corpses by healthy neighbors
or professional phagocytes. Efficient clearance of cells that have succumbed to apoptosis
is crucial for normal tissue homeostasis, and for the modulation of immune responses.
The disposal of apoptotic cells is finely regulated by a highly redundant system of
receptors, bridging molecules and 'eat me' signals. The complexity of the system is
reflected by the term: 'engulfment synapse', used to describe the interaction between
a phagocytic cell and its target. In healthy humans, dying neutrophils are the most
abundant and important targets for such recognition and engulfment. In inflammation
the scope and importance of this complicated task is further increased. Paradoxically,
despite growing evidence highlighting the priority of neutrophils clearance, the recognition
of these cells by phagocytes is not as well understood as the recognition of other
apoptotic cell types. New findings indicate that the interaction of phosphatidylserine
(PS) on apoptotic neutrophils with its receptor on macrophages is not as critical
for the specific clearance of neutrophil corpses it was previously believed. In this
review we focus on recent findings regarding alternative, PS-independent "eat me"
signals expressed on neutrophils during cell death and activation. Based on our own
research, we emphasize the clearance of dying neutrophils, especially at the focus
of bacterial infection; and the associated inflammatory reaction, which occurs in
a highly proteolytic milieu containing both host and bacteria-derived proteinases.
In these environments, eat-me signals expressed by neutrophils are drastically modified;
arguing against the phospholipid-based detection of apoptotic cells, but supporting
the importance of proteinaceous ligand(s) for the recognition of neutrophils by macrophages.
In this context we discuss the effect of the gingipain R (Rgp) proteinases from Porphyromonas
gingivalis on neutrophils interactions with macrophages. Since the recognition of
apoptotic neutrophils is an important fundamental process, serving multiple functions
in the regulation of immunity and homeostasis, we hypothesize that many pathogenic
bacteria may have developed similar strategies to confuse macrophage-neutrophil interaction
as a common pathogenic strategy.