Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors.
Fas ligand (FasL) is a potent proapoptotic type-II transmembrane protein that can cause cell death in Fas+ target populations. Despite the presumed "silent" nature of apoptotic cell death, forced expression of FasL can induce a dramatic inflammatory response. To elucidate the in vivo mechanism(s) linking FasL and inflammation, we used a membrane-bound cell-free form of FasL (mFasL-vesicle preparation (VP)). We found that i.p. injection of FasL-microvesicles led to the rapid activation and subsequent demise of Mac1(high) resident peritoneal macrophages. Apoptosis of Mac1(high) peritoneal macrophages was observed within 0.5 h of mFasL-VP injection and correlated with the detection of increased macrophage inflammatory protein (MIP)-2 levels in peritoneal lavage fluid as well as induced RNA expression of IL-1beta, MIP-2, MIP-1alpha, and MIP-1beta. In vitro culture of purified peritoneal populations identified Mac1(high) cells as the major cytokine/chemokine producers in response to mFasL-VP. Purified Mac1(high) cells exposed to FasL could restore the ability of Fas-deficient mice to mount an inflammatory response. Our data demonstrate that the FasL-mediated inflammatory response starts with the production of proinflammatory mediators by preapoptotic resident tissue macrophages and suggest a general mechanism responsible for neutrophil inflammation seen in cases of FasL-expressing allografts.
Hohlbaum
A M
AM
Department of Microbiology, School of Medicine, Boston University, Boston, MA 02118, USA.
Gregory
M S
MS
Ju
S T
ST
Marshak-Rothstein
A
A
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D001202:Ascitic Fluid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002469:Cell Separation; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D022162:Cytoplasmic Vesicles / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007940:Leukemia L5178; D008024:Ligands; D017737:Macrophages, Peritoneal / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008562:Membrane Glycoproteins / Q000378:metabolism* / Q000502:physiology; D051379:Mice; D008805:Mice, Inbred A; D008809:Mice, Inbred C3H; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D009368:Neoplasm Transplantation; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D009687:Nuclear Proteins; D014157:Transcription Factors; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
D018925:Chemokines; D002630:Chemotactic Factors; D016207:Cytokines; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D019014:fas Receptor