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Role of CCR2 in macrophage migration into the liver during acetaminophen‐induced hepatotoxicity in the mouse
Author(s) -
Dambach Donna M.,
Watson Linda M.,
Gray Kevin R.,
Durham Stephen K.,
Laskin Debra L.
Publication year - 2002
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1053/jhep.2002.33162
Subject(s) - ccr2 , acetaminophen , chemokine , monocyte , cd68 , macrophage , tumor necrosis factor alpha , inflammation , ccl2 , liver injury , knockout mouse , medicine , chemistry , receptor , chemokine receptor , pharmacology , immunohistochemistry , in vitro , biochemistry
The biological effects of monocyte chemoattractant protein (MCP) 1 are mediated by binding to C‐C chemokine receptor (CCR) 2. In the present studies, we used CCR2 knockout (CCR2−/−) mice to examine the role of MCP‐1 in acetaminophen‐induced macrophage accumulation in the liver, expression of inflammatory cytokines, and hepatotoxicity. We found that hepatic expression of CCR2 and MCP‐1 was increased 10‐fold and 20‐fold, respectively, 12 to 72 hours after administration of acetaminophen to wild‐type mice. Expression of these proteins was localized in centrilobular regions of the liver. Whereas MCP‐1 was expressed by both hepatocytes and macrophages, CCR2 was identified in inflammatory macrophages. F4/80 is a marker of mature macrophages expressed in large quantities by Kupffer cells. In wild‐type mice, a 75% decrease in F4/80‐positive macrophages was observed 24 to 48 hours after administration of acetaminophen. In contrast, expression of macrosialin (CD68), a marker of activated macrophages, increased 2‐fold 24 to 72 hours after administration of acetaminophen and was associated with inflammatory cells. Although there was a decrease in the overall severity of inflammation and in the number of macrosialin‐positive macrophages 72 hours after administration of acetaminophen in CCR2−/− mice, the number of F4/80‐positive cells did not change. Loss of CCR2 was also found to alter acetaminophen‐induced expression of tumor necrosis factor α, monocyte chemoattractant protein 3, and KC/gro. However, the overall outcome of acetaminophen‐induced hepatic injury was not affected. In conclusion, these data indicate that MCP‐1 and CCR2 contribute to the recruitment of a subset of activated macrophages into the liver during acetaminophen‐induced hepatotoxicity that may be important in resolution of tissue injury.