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-H transmembrane protein tha t can cause cell death in Fas(+) target populations. Despite the presumed " silent" nature of apoptotic cell death, forced expression of FasL can induc e a dramatic inflammatory response. To elucidate the in vivo mechanism(s) l inking FasL and inflammation, we used a membrane-bound cell-free form of Fa sL (mFasL-vesicle preparation (VP)). We found that i.p. injection of FasL-m icrovesicles led to the rapid activation and subsequent demise of Mac1(high ) resident peritoneal macrophages. Apoptosis of Mac1(high) peritoneal macro phages was observed within 0.5 h of mFasL-VP injection and correlated with the detection of increased macrophage inflammatory protein (MIP)-2 levels i n peritoneal lavage fluid as well as induced RNA expression of IL-1 beta, M IP-2, MIP-1 alpha, and MIP-1 beta. In vitro culture of purified peritoneal populations identified Mac1(high) cells as the major cytokine/chemokine pro ducers in response to mFasL-VP. Purified Mac1(high) cells exposed to FasL c ould restore the ability of Fas-deficient mice to mount an inflammatory res ponse. Our data demonstrate that the FasL-mediated inflammatory response st arts with the production of proinflammatory mediators by preapoptotic resid ent tissue macrophages and suggest a general mechanism responsible for neut rophil inflammation seen in cases of FasL-expressing allografts.