Kupffer cell expression of macrophage receptor with collagenous structure modulates macrophage gene induction and limits acute liver injury

Macrophages displaying a pro-repair and anti-inflammatory polarization have been implicated in resolution of acute liver injury. Macrophage receptor with collagenous structure (MARCO) expression marks tolerogenic hepatic macrophages and is expressed by pro-resolution macrophages in the injured liver. We tested the hypothesis that MARCO promotes repair of the acetaminophen (APAP)-injured liver. Robust and sustained induction of MARCO mRNA and protein expression was evident in livers of mice challenged with a hepatotoxic dose of APAP (i.e. 300 mg/kg), whereas hepatic MARCO induction failed in mice with APAP-induced liver failure (i.e. 600 mg/kg). Serum proteomics identified a significant increase in serum MARCO levels in surviving acute liver failure (ALF) patients, but not in ALF patients who died. MARCO expression was high in F480+ liver macrophages, and MARCO deficiency reduced macrophage expression of pro-resolution markers such as Gpnmb and Mertk during the repair phase (i.e. 48 h). The results suggested a delay in necrosis resolution along with a trend toward increased mortality in APAP-challenged MARCO-/- mice. Notably, a robust increase in peak hepatic injury (i.e. 6- to 24-h post-APAP challenge) was evident in MARCO-/- mice, which could not be ascribed to differences in NAPQI/APAP-adduct generation nor changes in hepatic neutrophil/macrophage numbers. Interestingly, a reduction in hepatic CD11c+ cells, shown previously to limit APAP-induced liver injury, was evident 24 h after APAP challenge in MARCO-/- mice. The results indicate that MARCO deficiency worsens APAP-induced acute liver injury in mice and provide experimental and initial translational evidence linking MARCO induction to positive outcomes in acute liver injury.