Fas Ligand Engagement of Resident Peritoneal Macrophages In Vivo Induces Apoptosis and the Production of Neutrophil Chemotactic Factors

• Published in: The Journal of immunology (1950) 2001-12, Vol.167 (11), p.6217-6224
• Main Authors: Hohlbaum, Andreas M, Gregory, Meredith S, Ju, Shyr-Te, Marshak-Rothstein, Ann
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis - genetics; Apoptosis - immunology; Ascitic Fluid - immunology; Ascitic Fluid - metabolism; Ascitic Fluid - pathology; Cell Separation; Chemokines - biosynthesis; Chemokines - genetics; Chemokines - metabolism; Chemotactic Factors - biosynthesis; Chemotactic Factors - genetics; Cytokines - biosynthesis; Cytokines - genetics; Cytokines - metabolism; Cytoplasmic Vesicles - immunology; Fas Ligand Protein; fas Receptor - genetics; fas Receptor - metabolism; FasL protein; Female; Gene Expression Regulation - immunology; Inflammation - immunology; Leukemia L5178; Ligands; macrophage inflammatory protein 2; Macrophages, Peritoneal - immunology; Macrophages, Peritoneal - metabolism; Macrophages, Peritoneal - pathology; Membrane Glycoproteins - metabolism; Membrane Glycoproteins - physiology; Mice; Mice, Inbred A; Mice, Inbred C3H; Mice, Inbred DBA; Mice, Inbred MRL lpr; Mice, Mutant Strains; Neoplasm Transplantation; Neutrophils - immunology; Neutrophils - metabolism; Nuclear Proteins; Transcription Factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.167.11.6217

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.