Roth K, Strickland J, Joshi N, et al. - Researchers inquired the hypothesis that the fibrinolytic enzyme, plasmin, is a key regulator of macrophage function following acetaminophen (APAP)-induced liver injury. The up-regulation of proinflammatory cytokines following APAP overdose was prolonged due to inhibition of plasmin in mice with tranexamic acid. In culture, plasmin directly, and in synergy with high-mobility group B1, stimulated Kupffer cells and bone marrow-derived macrophages to generate cytokines by a mechanism that needed NF-κB. Repression of plasmin in vivo also limited the trafficking of monocyte-derived macrophages into necrotic lesions following APAP overdose. This inhibited phagocytic removal of dead cells, arrested maturation of monocyte-derived macrophages into F4/80-expressing macrophages, and restricted finishing of proinflammatory cytokine production. The studies further exhibit that phagocytosis is a significant stimulus for the suspension of proinflammatory cytokine production as treatment of proinflammatory, monocyte-derived macrophages, isolated from APAP-treated mice, with necrotic hepatocytes reduced expression of proinflammatory cytokines. Altogether, these studies illustrate that plasmin is a significant regulator of macrophage function following APAP overdose.