Fas ligand (gld)- and Fas (lpr)-deficient mice do not show alterations in the extravasation or apoptosis of inflammatory neutrophils.
Apoptosis of neutrophils plays a critical role in the resolution of acute inflammation. Neutrophils from human peripheral blood express Fas (CD95) and are sensitive to Fas ligand (FasL)/Fas-mediated apoptosis. Mice carrying spontaneous mutations in the genes for fas ligand (B6/gld) or fas (B6/lpr) were used to assess the role of FasL/Fas in the kinetics and magnitude of neutrophil extravasation to the thioglycolate (TG)-inflamed peritoneum and in the spontaneous apoptosis of TG-elicited neutrophils. The results showed that TG-elicited neutrophils (defined by flow cytometry as GR-1/Ly-6G(hi) cells) from normal (B6) and B6/gld mice, but not from the Fas-deficient B6/lpr mice, express high levels of Fas. The TG-elicited neutrophil response began at 2 h, peaked at 4 h, and subsided by 24-48 h after TG administration in all three strains. However, the response was more prolonged in B6 mice, such that B6/gld and B6/lpr mice had fewer neutrophils at 6 h after TG administration than did B6 mice. Further studies showed that 4 h TG-elicited neutrophils from B6, B6/gld and B6/lpr mice undergo apoptosis in vitro at similar rates (as assessed through flow cytometry by the decrease in forward angle light-scatter and externalization of phosphatidylserine (PS; as detected by Annexin V-FITC) that occur as neutrophils undergo apoptosis). Fas expression was down-regulated on apoptotic neutrophils in conjunction with maximal PS externalization and decreased forward angle light-scatter. Collectively, these findings suggest that FasL/Fas-mediated apoptosis is not essential in regulating the lifespan of neutrophils during an acute inflammatory response. The abbreviated inflammatory response observed in FasL/Fas-deficient mice is likely to be a secondary effect of the gld/lpr autoimmune/lymphoproliferative syndrome, and not a direct effect of FasL/Fas on the ability of inflammatory neutrophils to undergo apoptosis.
Fecho
K
K
Department of Medicine, University of North Carolina at Chapel Hill, 27599-7280, USA.
Cohen
P L
PL
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D005119:Extravasation of Diagnostic and Therapeutic Materials; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D006801:Humans; D007249:Inflammation / Q000097:blood / Q000473:pathology*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D009504:Neutrophils / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D013864:Thioglycolates / Q000494:pharmacology; D013997:Time Factors; D019014:fas Receptor / Q000096:biosynthesis / Q000502:physiology*
C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D013864:Thioglycolates; D019014:fas Receptor