The multifaceted role of macrophages during acute liver injury

Abstract

The liver is situated at the interface of the gut and circulation where it acts as a filter for blood-borne and gut-derived microbes and biological molecules, promoting tolerance of non-invasive antigens while driving immune responses against pathogenic ones. Liver resident immune cells such as Kupffer cells (KCs), a subset of macrophages, maintain homeostasis under physiological conditions. However, upon liver injury, these cells and others recruited from circulation participate in the response to injury and the repair of tissue damage. Such response is thus spatially and temporally regulated and implicates interconnected cells of immune and non-immune nature. This review will describe the hepatic immune environment during acute liver injury and the subsequent wound healing process. In its early stages, the wound healing immune response involves a necroinflammatory process characterized by partial depletion of resident KCs and lymphocytes and a significant infiltration of myeloid cells including monocyte-derived macrophages (MoMFs) complemented by a wave of pro-inflammatory mediators. The subsequent repair stage includes restoring KCs, initiating angiogenesis, renewing extracellular matrix and enhancing proliferation/activation of resident parenchymal and mesenchymal cells. This review will focus on the multifaceted role of hepatic macrophages, including KCs and MoMFs, and their spatial distribution and roles during acute liver injury.

Keywords: acute injury; liver; macrophages; necroinflammation; spatial distribution; tissue repair; wound healing response.

Figure 1

Schematic representations of a classical liver lobule and sinusoids. (A) The classical liver lobule has a hexagon-like structure. It is composed of a central vein surrounded by portal triads. Each portal triad is composed of a portal venule, a hepatic artery and a bile duct. (B) the insert, Central veins connect to portal veins via sinusoids which are capillary vessels where oxygen-rich blood from the hepatic artery mixes with the nutrient-rich blood from the portal vein and is delivered to the central vein. They are lined by a layer of fenestrated LSECs allowing the communication between sinusoidal blood and the perisinusoidal space of Disse and hepatocytes. KCs, the hepatic resident macrophages are located inside the sinusoids. KCs are strategically located adjacent to fenestrated LSECs to ensure clearing of portal blood from bacteria, viruses, immune complexes, effete proteins and lipids via their phagocytic activity and cytokine production. HSCs are residents of the space of Disse and exhibit a quiescent state under homeostasis. They are responsible of Vitamin A storage and metabolism. Under homeostatic conditions, few monocyte-derived macrophages (MoMFs) could be also distinguished. Liver capsular macrophages (LCMs), located in the hepatic capsule, sense and prevent the translocation of bacteria from the peritoneum into the liver. Non-classical monocytes (NCMs) patrol endothelial cells of sinusoids and are responsible for repairing vessel damage. Created using Biorender.com.

Figure 2

Schematic representation of the wound healing response during toxin-induced acute liver injury. The first response phase termed necroinflammation, is characterized by the death of pericentral hepatocytes, a partial depletion of hepatic lymphocytes, decrease of Kupffer cells, the influx of myeloid cells, namely Ly6C^hiCX3CR1^- inflammatory monocytes, differentiated Ly6C⁺CX3CR1⁺ MoMFs, non-classical monocytes (NCMs), and a first wave of neutrophils, and the release of pro-inflammatory cytokines and chemokines, including IL-1β and TNF-α. Subsequently, during the early repair, MoMFs further differentiate and proliferate, they relocate to the inner necrotic regions around central veins and participate to the activation of HSCs and the clearing of dead hepatocytes. KCs proliferate from remaining KCs and repopulate the outermost regions of the injury around central veins. A second wave of infiltrating neutrophils contribute to injury repair by clearing dead cell debris and release of ROS. During late repair, MoMFs and neutrophils are depleted, and the cluster of KCs and HSCs around central veins dissipate to re-establish the homeostatic spatial distribution of resident cell subsets.