BMJ Open Gastro 2016; 3:e000079 doi:10.1136/bmjgast-2016-000079
Hepatic macrophages in liver fibrosis: pathogenesis and potential therapeutic targets
Hai Li1, Hong You2, Xu Fan3, Jidong Jia2,
Author Affiliations
1Department of Hepatopancreatobiliary and Splenic Medicine, Affiliated Hospital, Logistics University of People's Armed Police Force, Tianjin, People's Republic of China
2Liver Research Center, Beijing Friendship Hospital, Capital Medial University, Beijing, People's Republic of China
3State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing, People's Republic of China
Received:
10 January 2016
Accepted:
18 April 2016
Published Online:
25 May 2016
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Abstract
Hepatic macrophages account for the largest non-parenchymal cell population in the liver. Recent studies have found that hepatic macrophages have different functions in different stages of experimental liver fibrosis. Some studies found that there are different types of hepatic macrophages in the liver, although others have suggested that hepatic macrophages could switch to different phenotypes in different environments. Many studies demonstrated that while hepatic macrophages promoted fibrosis through the recruitment of proinflammatory immune cells, and the secretion of proinflammatory cytokines and chemokines in the early stages, these also promoted the resolution of hepatic fibrosis through the secretion of matrix metalloproteinases in the late stages. This article will review the current role played by hepatic macrophages in liver fibrosis and the potential therapeutic targets that modulate hepatic macrophages.
Keywords: HEPATIC FIBROSIS, MACROPHAGES, IMMUNOLOGY IN HEPATOLOGY
Potential targets of hepatic macrophages to treat liver fibrosis
Hepatic macrophages engage in close interactions with other non-parenchymal cells of the liver, especially HSCs.35 36 TGF-β1 and platelet derived growth factor (PDGF) secreted by hepatic macrophages can activate HSCs to fibroblasts, and the latter can proliferate and secrete abundant collagens and other ECM, thereby causing liver fibrosis.37
As hepatic macrophages have such great variability and huge numbers (10–15% of total liver cells), and also play important regulatory roles, these cells offer potential targets for treating liver fibrosis.
The first target involves preventing the infiltration of inflammatory mononuclear cells (Ly-6C+) through the inhibition of CCL2 (MCP-1) by RNA molecular technology,38 cleaning the intestinal tract with antibiotics to reduce the exposure of the liver to endotoxin, thereby reducing the infiltration of inflammatory cells.15 38–40
The second target involves antagonising the inflammatory cytokines released from hepatic macrophages, such as IL-1 and TNF-α,41 or promoting the apoptosis of activated HSCs, thereby attenuating hepatic fibrosis.42 43
The third target involves modulating the functional switch of hepatic macrophages via biological engineering of macrophages by nanoparticles44 45 or targeting drugs (dexamethasone vesicles) to control the functional transformation of hepatic macrophages.46
The fourth target involves promoting the functional restoration of macrophages by using CX3CL1 and IL-4 to accelerate the resolution of liver fibrosis.31 An ex vivo approach entails culturing peripheral blood monocytes in vitro under conditions favouring restorative hepatic macrophages47 or other desired subtypes48 and then intravenously infusing the cells back into patients to alleviate liver fibrosis.49
Hepatic macrophages play a key role in the progression and regression of fibrosis, although there are still many unanswered questions that need further investigation. Finally, tailored yet standardised methods for the purification and identification of functionally heterogeneous hepatic macrophages are urgently needed to yield reproducible and communicable results that shed light on the pathogenesis of liver fibrosis and offer novel potential therapeutic targets for liver fibrosis.3 30