Ample evidence suggests that hepatic macrophages play key roles in the injury and repair mechanisms during liver disease progression. There are two major populations of hepatic macrophages: the liver resident Kupffer cells and the monocyte-derived macrophages, which rapidly infiltrate the liver during injury. Under different disease conditions, the tissue microenvironmental cues of the liver critically influence the phenotypes and functions of hepatic macrophages. Furthermore, hepatic macrophages interact with multiple cells types in the liver, such as hepatocytes, neutrophils, endothelial cells, and platelets. These crosstalk interactions are of paramount importance in regulating the extents of liver injury, repair, and ultimately liver disease progression. In this review, we summarize the novel findings highlighting the impact of injury-induced microenvironmental signals that determine the phenotype and function of hepatic macrophages. Moreover, we discuss the role of hepatic macrophages in homeostasis and pathological conditions through crosstalk interactions with other cells of the liver.

The liver can fully regenerate after partial resection, and its underlying mechanisms have been extensively studied. The liver can also rapidly regenerate after injury, with most studies focusing on hepatocyte proliferation; however, how hepatic necrotic lesions during acute or chronic liver diseases are eliminated and repaired remains obscure. Here, we demonstrate that monocyte-derived macrophages (MoMFs) were rapidly recruited to and encapsulated necrotic areas during immune-mediated liver injury and that this feature was essential in repairing necrotic lesions. At the early stage of injury, infiltrating MoMFs activated the Jagged1/notch homolog protein 2 (JAG1/NOTCH2) axis to induce cell death–resistant SRY-box transcription factor 9⁺ (SOX9⁺) hepatocytes near the necrotic lesions, which acted as a barrier from further injury. Subsequently, necrotic environment (hypoxia and dead cells) induced a cluster of complement 1q–positive (C1q⁺) MoMFs that promoted necrotic removal and liver repair, while Pdgfb⁺ MoMFs activated hepatic stellate cells (HSCs) to express α–smooth muscle actin and induce a strong contraction signal (YAP, pMLC) to squeeze and finally eliminate the necrotic lesions. In conclusion, MoMFs play a key role in repairing the necrotic lesions, not only by removing necrotic tissues, but also by inducing cell death–resistant hepatocytes to form a perinecrotic capsule and by activating α-smooth muscle actin–expressing HSCs to facilitate necrotic lesion resolution.

Eosinophils protect against liver injury during orthotopic liver transplantation and other conditions of hepatic ischemia-reperfusion injury in mice.