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Review
. 2023 Oct 26:14:1279264.
doi: 10.3389/fimmu.2023.1279264. eCollection 2023.

The role and mechanisms of macrophage polarization and hepatocyte pyroptosis in acute liver failure

Dan Xie  1 , Shi Ouyang  1
Affiliations
Review

The role and mechanisms of macrophage polarization and hepatocyte pyroptosis in acute liver failure

Dan Xie et al. Front Immunol. .

Abstract

Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.

Keywords: acute liver failure (ALF); immune; macrophage; polarization; pyroptosis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The Unique Anatomy of the Liver. The liver has a unique anatomy in that it receives blood from both the hepatic artery and the portal vein. Both sets of blood supplies end in liver sinusoidal endothelial cells (LSEC) with a large number of Kupffer cells (KCs) attached to their surface. When the blood flows through this area, it moves slowly in sinusoidal waves at a slow pace. This allows for the effective absorption of nutrients and nourishment of the liver tissues. Additionally, it enables the attached KCs to remove disease-causing substances, thereby maintaining the body’s homeostasis.
Figure 2
Figure 2
The Phenotypes and Pathways of Macrophage Polarization. Primary macrophages can differentiate into pro-inflammatory (M1) and anti-inflammatory (M2) macrophages by activating various factors and pathways. Among them, factors such as LPS, interferon-γ (IFN-γ), and tumor necrosis factor-α (TNF-α) can induce the differentiation of primitive macrophages into M1-type macrophages, i.e., classically activated macrophages (CAMs), through activation of the TLR/NF-κB, JAK1,2/STAT1, and Notch signaling pathways. These M1-type macrophages produce a large number of pro-inflammatory factors, such as interleukin (IL)-1β, reactive oxygen species (ROS), and TNF-α, further inducing a proinflammatory response. In contrast, when anti-inflammatory factors such as IL-4, IL-13, and IL-10 activate the JAK/STAT3, STAT6, and TGF-β/Smads signaling pathways, they induce the differentiation of M2-type macrophages, also known as alternatively activated macrophages (AAMs). These macrophages produce anti-inflammatory factors such as IL-10, TGF-β, and Arg-1, which initiate an anti-inflammatory response.
Figure 3
Figure 3
The Mechanisms of CAMs Formation. Notch receptors, which are expressed on the surface of macrophages, bind to neighboring cellular ligands. The ligand-receptor complex is formed and then exposed to hydrolysis site 2 (S2) in the extracellular proximal membrane region after endocytosis. After cleavage by tumor necrosis factor-α-converting enzyme (TACE) and hydrolysis of the γ-secretase complex (located at site S3 in the transmembrane region), a soluble Notch intracellular domain (NICD) is formed. This NICD then enters the cytoplasm and translocates to the nucleus, where it binds to the nuclear CSL transcription factor complex. This binding further activates Hes and Hey, induces the formation of CAMs, and mediates the release of inflammatory factors. On the other hand, the interferon-γ (IFN-γ) receptor (IFN-γR) on the surface of macrophages activates JAK1/JAK2 upon IFN-γ stimulation, which leads to the phosphorylation of intracellular STAT1. Phosphorylated STAT1 then enters the nucleus and binds to the Gamma interferon activation site (GAS) DNA element. This binding induces the transcription of interferon-stimulated genes (ISGs) and triggers the formation of CAMs.
Figure 4
Figure 4
The Mechanisms of Pyroptosis. In the canonical pathway of pyroptosis, Toll-like receptors (TLRs) recognize extracellular pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), leading to the formation of inflammasomes. This, in turn, activates pro-caspase-1, causing it to mature into caspase-1. Caspase-1 is then released into the cytoplasm and acts on the NF-κB signaling pathway, promoting the maturation of IL-1β and IL-18. Secondly, activated caspase-1 cleaves the gasdermin D (GSDMD) protein into N-terminal and C-terminal fragments. The N-GSDMD fragments form pore membranes on the cell surface, allowing the release of IL-1β and IL-18 from the cell, thereby triggering inflammatory responses. Cell contents can also flow out through the pore membrane, resulting in an imbalance of intracellular and extracellular fluids and rapid cell lysis. In the non-canonical pathway, extracellular LPS can directly enter the cell and bind to the CARD domain on the intracellular Caspase-4/5/11 precursor, promoting the activation of mature Caspase-4/5/11. This activation leads to the formation of the N-GSDMD pore membrane, which triggers cellular pyroptosis. Additionally, it activates the ATP membrane channel, pannexin-1, which leads to the release of ATP from the cell. ATP binds to the P2X7 receptor through autocrine or paracrine mechanisms, resulting in the opening of the P2X7 pore. This leads to the release of cellular contents and ultimately triggers pyroptosis.
Figure 5
Figure 5
The Crosstalk of Pyroptosis and Macrophage Polarization in ALF. Macrophage polarization and hepatocyte pyroptosis play important roles in acute liver failure (ALF). The mutual crosstalk and regulation between these two processes can impact the progression of the disease. However, the specific mechanisms involved require further study and exploration. “?”: there are many unknown relationships between macrophage polarization and hepatocyte pyroptosis in ALF that need to be further explored and investigated in the future, including the impact of their mutual regulation and constraints on disease progression in ALF as well as the specific pathways of action.
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Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (81803884), Plan on enhancing scientific research in GMU (02-410-2302092XM), 2022 Guangzhou Medical University discipline construction projects (02-410-2206013), the 2022 Student Innovation Capacity Enhancement Program Project of Guangzhou Medical University (02-408-2304-19064XM), 2023 City school (college) enterprise joint funding projects (2023A03J0421), the Undergraduate Capacity Enhancement Innovation Project of Guangzhou Medical University (2022JXA003), the 2023 Artificial Liver Special Fund (iGandanF-1082023-RGG023), the Key Medical Discipline of Guangzhou [2021-2023] and the Key Laboratory of Guangdong Higher Education Institutes (2021KSYS009).

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