Here, Miyamoto et al. show that gut commensals induce MARCO+IL-10+ macrophages that protect the liver. Initially, the authors found that compared with pericentral vein (CV) zones, periportal vein (PV) zones in mouse liver are enriched in pathways linked to negative immune regulation. Imaging of laser-damaged livers showed that neutrophils preferentially accumulate at CV zones, rather than PV zones. However, depletion of liver macrophages led to equal accumulation of neutrophils in both zones, which suggests that a suppressive macrophage subset resides in the PV zone.

The authors confirmed that PV zones are enriched in Kupffer cells (KCs; liver-resident macrophages) that express anti-inflammatory genes, such as Il10, Il1rn and Tgfb1, and the scavenger receptor MARCO. Public datasets identified similar MARCO+IL-10+ KCs in the human liver and these cells were reduced in patients with liver cirrhosis. The MARCO+IL-10+ KCs were found to be the major source of IL-10 in the liver, and blocking their production of IL-10 increased neutrophil adhesion in PV zones. Furthermore, this IL-10 production was shown to depend on MARCO-mediated scavenging of bacteria.