A role for splenic monocytes/macrophages in acetaminophen-induced hepatotoxicity (P5140)

Abstract

Abstract Activated macrophages (MP) has been implicated in hepatotoxicity induced by the analgesic acetaminophen (APAP). However, the origin of these cells is unknown. Here, we analyzed the role of splenic monocytes (Mo)/MP in APAP-induced liver inflammation and injury. Treatment of mice with APAP (300 mg/kg, i.p.) was associated with a time-related increase in CD11b+Ly6Chi pro-inflammatory MP in the liver after 24-96 h. In the spleen, but not the BM, this was correlated with a significant increase in the number and proliferative activity of CD11b+F4/80+Ly6Chi inflammatory Mo/MP. CD11b+F4/80-Ly6Chi inflammatory Mo/MP were also found to increase in the spleen, as well as in the BM 72-96 h post-APAP. Conversely, CD11b+F4/80+Ly6Clo anti-inflammatory Mo/MP decreased in the spleen after 48-96 h. To assess the role of splenic Mo/MP in APAP hepatotoxicity, we used splenectomized (spx) mice. APAP-induced hepatotoxicity was significantly reduced in spx mice, as measured by decreases in serum transaminases, and histological evidence of hepatic necrosis. This was associated with a decrease in pro-inflammatory Gal-3+ MP in the liver, and an increase in CX3CR1 and CCR2 expression, proteins important in recruiting anti-inflammatory MP into the liver following APAP-induced injury. Taken together, these results indicate that the spleen is a site of monocytopoiesis and that splenic Mo/MP contribute to inflammation and hepatotoxicity induced by APAP.