Abstract
Chemokines are a family of cytokines that orchestrate the migration and positioning of immune cells within tissues and are critical for the function of the immune system. CCR2 participates in liver pathology, including acute liver injury, chronic hepatitis, fibrosis/cirrhosis, and tumor progression, by mediating the recruitment of immune cells to inflammation and tumor sites. Although a variety of chemokines have been well studied in various diseases, there is no comprehensive review presenting the roles of all known chemokine ligands of CCR2 (CCL2, CCL7, CCL8, CCL12, CCL13, CCL16, and PSMP) in liver disease, and this review aims to fill this gap. The introduction of each chemokine includes its discovery, its corresponding chemotactic receptors, physiological functions and roles in inflammation and tumors, and its impact on different immune cell subgroups.
Highlights
Chemokines are a large family of small, highly conserved secretory proteins composed of nearly 50 cytokines [1]
After the liver is damaged by viral infections, alcohol abuse, or metabolic disorders, liver cells, such as hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs), secrete C motif chemokine ligand 2 (CCL2), which recruits many circulating chemokine receptor 2 (CCR2)+ monocytes to the injured liver [6–8, 15, 16]
The expression of PC3-secreted microprotein (PSMP) was markedly increased in human cirrhotic and hepatocellular carcinoma (HCC)-adjacent liver tissues [32]. These results suggest that PSMP may play an essential role in other liver diseases by regulating immune cells and HSCs, warrants further investigation
Summary
Chemokines are a large family of small, highly conserved secretory proteins composed of nearly 50 cytokines [1]. CCR2 can promote liver fibrosis by regulating the migration of circulating monocytes to the injured liver and through activation of hepatic stellate cells (HSCs) [7, 8]. Both preclinical and clinical studies have shown that a dual CCR2/CCR5 antagonist, cenicriviroc (CVC), is an effective and safe antifibrotic agent for treating nonalcoholic steatohepatitis (NASH) and alcoholinduced steatohepatitis [9–12]. As we summarize, CCR2 is a high-affinity receptor for members of the monocyte chemotactic protein (MCP) family, including C-C motif chemokine ligand 2 (CCL2), CCL7, CCL8, CCL12 (mouse only), and CCL13 (human only) [33–37]. CCL2 promotes cancer cell migration and invasion by activating the p38 MAPK pathway, leading to tumor metastasis [42]. CCL8 can promote endothelial cell migration, proliferation, and angiogenesis through CCR2 by activating the extracellular signal-regulated kinase (ERK) 1/2 signaling pathway [48, 49]
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