Role of resident peritoneal macrophages and mast cells in chemokine production and neutrophil migration in acute inflammation: Evidence for an inhibitory loop involving endogenous IL-10

The roles played by resident macrophages (M phi) and mast cells (MCs) in po lymorphonuclear leukocyte (PMN) accumulation and chemokine production withi n the mouse peritoneal cavity in response to administration of zymosan (0.2 and 1 mg), LPS (1 mg/kg), and thioglycolate (0.5 ml of a 3% suspension) we re investigated. A marked reduction (>95%) in intact MC numbers was obtaine d by pretreatment with the MC activator compound 48/80, whereas resident M phi were greatly diminished (>85%) by a 3-day treatment with liposomes enca psulating the cytotoxic drug dichloromethylene-bisphosphonate. No modulatio n of thioglycolate-induced inflammation was seen with either pretreatment, Removal of either MCs or M phi attenuated LPS-induced PMN extravasation wit hout affecting the levels of the chemokines murine monocyte chemoattractant protein-1 and KC measured in the lavage fluids. In contrast, MC depletion inhibited PMN accumulation and murine monocyte chemoattractant protein-1 an d KC production in the zymosan peritonitis model. Removal of M phi augmente d the accumulation of PMN elicited by the latter stimulus, This was due to an inhibitory action of M phi-derived IL-IO because there was 1) a time-dep endent release of IL-10 in the zymosan exudates; 2) a reduction in IL-10 le vels following M phi, but not MC, depletion; and 3) an increased PMN influx and chemokine production in IL-10 knockout mice. In conclusion, we propose a stimulus-dependent role of resident MCs in chemokine production and the existence of a regulatory loop between endogenous IL-10 and the chemokine-m ediated cellular component of acute inflammation.