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 ac ute 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/gl d) or fas (B6/lpr) were used to assess the role of FasL/Fas in the kin etics and magnitude of neutrophil extravasation to the thioglycolate ( TG)-inflamed peritoneum and in the spontaneous apoptosis of TG-elicite d neutrophils, The results showed that TG-elicited neutrophils (define d by flow cytometry as GR-1/Ly-6G(hi) cells) from normal (B6) and B6/g ld mice, but not from the Fas-deficient B6/lpr mice, express high leve ls 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 str ains. Ho However, the response was more prolonged in B6 mice, such tha t B6/gld and B6/lpr mice had fewer neutrophils at 6 h after TG adminis tration 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 las assessed through flow cytometry by the decrease in forward angle light-scatter and externalization of phosphatidylseri ne (PS; as detected by Annexin V-FITC) that occur as neutrophils under go apoptosis), Fas expression was downregulated on apoptotic neutrophi ls in conjunction with maximal PS externalization and decreased forwar d 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 inf lammatory response observed in FasL/Fas-deficient mice is likely to be a secondary effect of the gld/lpr autoimmune/lymphoproliferative synd rome, and not a direct effect of FasL/Fas on the ability of inflammato ry neutrophils to undergo apoptosis.