Inflammatory neutrophils retain susceptibility to apoptosis mediated via the Fas death receptor.
Apoptosis and clearance of neutrophils is essential for successful resolution of inflammation. Altered signaling via the Fas receptor could explain the observed prolongation of neutrophil lifespan and associated tissue injury at inflammatory sites. We therefore compared inflammatory neutrophils extracted from joints of rheumatoid arthritis patients, with peripheral blood neutrophils. Inflammatory neutrophils underwent constitutive apoptosis in culture more rapidly than peripheral blood neutrophils; this was not explained by changes in surface expression of Fas or by induction of Fas ligand. Inflammatory neutrophils remained sensitive to Fas-induced death, at levels comparable to those seen in peripheral blood neutrophils. Similarly, granulocyte-macrophage colony-stimulating factor reduced apoptosis but did not abolish signaling via Fas. These data provide evidence for the rate of apoptosis in inflammatory neutrophils being continually modulated by death and survival signals in the inflammatory milieu. This allows for rapid resolution of inflammation as levels of survival factors fall, and suggests new strategies for inducing resolution of inflammation.
Renshaw
S A
SA
Respiratory Medicine, University of Sheffield, Royal Hallamshire Hospital, United Kingdom.
Timmons
S J
SJ
Eaton
V
V
Usher
L R
LR
Akil
M
M
Bingle
C D
CD
Whyte
M K
MK
D017209:Apoptosis / Q000502:physiology*; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D002470:Cell Survival; D053222:Fas Ligand Protein; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation; D020014:K562 Cells; D008562:Membrane Glycoproteins / Q000097:blood / Q000502:physiology*; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D009504:Neutrophils / Q000166:cytology* / Q000276:immunology / Q000502:physiology*; D011480:Protease Inhibitors / Q000494:pharmacology; D012016:Reference Values; D015398:Signal Transduction; D019014:fas Receptor / Q000097:blood / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D011480:Protease Inhibitors; D019014:fas Receptor; D008666:Metalloendopeptidases