Trends in Immunology
ReviewNeutrophil clearance: when the party is over, clean-up begins
Section snippets
Removal of neutrophils from the circulation and after tissue deployment
Neutrophils are the most numerous of circulating leukocytes, and are readily mobilized innate immune cells that are crucial for defense against bacterial and fungal pathogens [1]. These terminally differentiated cells are short-lived; their lifespans are generally measured in terms of hours, although a recent and provocative report suggests a circulation time in the blood of several days 2, 3, 4. Neutrophils are continuously replenished during homeostasis, and their provision is augmented
Neutrophil ‘fates’: dead, activated or aged
Cell death is an irreversible endpoint, but lacks a precise definition, and could be considered to have occurred when: (i) plasma membrane integrity is lost; (ii) the cell fragments into discrete bodies; or (iii) the cell is engulfed by an adjacent cell 13, 14. Although neutrophil longevity during inflammation might be extended by various stimuli including pattern recognition signals, growth factors or chemokines, it can also be shortened following phagocytosis of a number of pathogens
‘Palatability’ of neutrophils, and their efferocytosis by macrophages
The process of cell corpse removal, called efferocytosis (‘to carry to the grave’) has been best studied with regard to the signals and mechanics involved in the removal of apoptotic cells, including apoptotic neutrophils. Colloquially, these signals have been designated as ‘find-me’ signals that attract macrophages to the site of cellular demise, and ‘eat-me’ signals on the apoptotic cell surface that often cluster into signaling platforms (Table 1, Figure 3) 12, 35. Of the known ‘eat-me’
Milieu and macrophage programming in efferocytosis of neutrophils
Aside from signals on the neutrophil itself, efferocytosis depends on factors in the microenvironment and the status of macrophage programming, which determines their readiness to engulf 55, 56, 57. First, availability of bridge molecules is crucial. For example, efferocytosis is much more efficient in the presence of serum in vitro, and presumably proteins in the interstitial fluid and inflammatory exudate contribute in vivo. Notably, some bridge molecules are tissue specific, for example,
Consequences of apoptotic neutrophil recognition
The consequences of neutrophil recognition and removal depend on neutrophil fate, the signals generated, programming of macrophages, and the playing field in which these events take place. Given the size of this subject, only a few outcomes are highlighted below and the reader is directed to several recent references 18, 31, 32, 54, 67, 70, 71.
Physical removal of neutrophils is the most obvious consequence of recognition by macrophages, and is required to return tissues to their normal
Concluding remarks
Undeniably, the primary function of neutrophils is host defense that, in turn, depends on adequate numbers in circulation and timely recruitment to sites of bacterial and fungal invasion. Once sterilization is accomplished, removal of neutrophils is imperative for the return of tissues to their functional state and to prevent further injury as these short-lived cells die and lose integrity. Aside from antimicrobial duties, neutrophils are also recruited during acute inflammation (e.g. in
Acknowledgments
The authors wish to thank Ms. Brenda Sebern for preparation of the manuscript. This work was funded by HL34303, GM61031, HL68864, HL81151.
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