Fas ligand engagement of resident peritoneal macrophages in vivo induces apoptosis and the production of neutrophil chemotactic factors

AM Hohlbaum, MS Gregory, ST Ju… - The Journal of …, 2001 - journals.aai.org
AM Hohlbaum, MS Gregory, ST Ju, A Marshak-Rothstein
The Journal of Immunology, 2001journals.aai.org
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 ip injection of FasL-
microvesicles led to the rapid activation and subsequent demise of Mac1 high resident …
Abstract
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 ip 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-1β, MIP-2, MIP-1α, and MIP-1β. 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.
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