Role of Bone Marrow Derived Macrophages in Acetaminophen‐induced Injury

Acetaminophen (APAP) is a widely used analgesic that causes centrilobular hepatic necrosis in toxic doses. Macrophages (MP) are known to contribute to APAP toxicity, participating in both proinflammatory and antiinflammatory/wound repair processes. Herein, we analyzed the origin of the cells. Bone marrow chimeric mice were generated using green fluorescent protein (GFP+) mice as donors. Flow cytometric analysis revealed that the bone marrow cells from chimeric mice were more than 80% GFP + . Following APAP administration we observed an increase in GFP + CD11b + in the liver beginning at 24 h, and persisting for 96 h. These cells were found to consist of immature (F4/80 ‐ ) and mature (F4/80 + ) Ly6C hi proinflammatory and Ly6C lo anti‐inflammatory MP; the majority of Ly6C hi MP were F4/80 ‐ , while Ly6C lo MP consisted of mature and immature cells. Ly6C lo MP were found to increase in the liver 72‐96 h after APAP, a time coordinate with tissue repair. Analysis of liver sections confirmed the accumulation of mature F4/80 + GFP + MP in the livers of APAP treated mice. Findings that these cells did not express mannose receptor, a marker of anti‐inflammatory MP, support the idea that bone marrow derived pro‐ and anti‐inflammatory MP subpopulations accumulating in the liver are distinct. Grant support: NIH AR055073; ES005022.