Title: Role of galectin-3 in classical and alternative macrophage activation in the liver following acetaminophen intoxication.

Authors: Dragomir, Ana-Cristina Docan; Sun, Richard; Choi, Hyejeong; Laskin, Jeffrey D; Laskin, Debra L

Published In J Immunol, (2012 Dec 15)

Abstract: Inflammatory macrophages have been implicated in hepatotoxicity induced by the analgesic acetaminophen (APAP). In these studies, we characterized the phenotype of macrophages accumulating in the liver following APAP intoxication and evaluated the role of galectin-3 (Gal-3) in macrophage activation. Administration of APAP (300 mg/kg, i.p.) to wild-type mice resulted in the appearance of two distinct subpopulations of CD11b(+) cells in the liver, which expressed high or low levels of the monocyte/macrophage activation marker Ly6C. Whereas CD11b(+)/Ly6C(hi) macrophages exhibited a classically activated proinflammatory phenotype characterized by increased expression of TNF-α, inducible NO synthase, and CCR2, CD11b(+)/Ly6C(lo) macrophages were alternatively activated, expressing high levels of the anti-inflammatory cytokine IL-10. APAP intoxication was also associated with an accumulation of Gal-3(+) macrophages in the liver; the majority of these cells were Ly6C(hi). APAP-induced increases in CD11b(+)/Ly6C(hi) macrophages were significantly reduced in Gal-3(-/-) mice. This reduction was evident 72 h post APAP and was correlated with decreased expression of the classical macrophage activation markers, inducible NO synthase, IL-12, and TNF-α, as well as the proinflammatory chemokines CCL2 and CCL3, and chemokine receptors CCR1 and CCR2. Conversely, numbers of CD11b(+)/Ly6C(lo) macrophages increased in livers of APAP-treated Gal-3(-/-) mice; this was associated with increased expression of the alternative macrophage activation markers Ym1 and Fizz1, increased liver repair, and reduced hepatotoxicity. These data demonstrate that both classically and alternatively activated macrophages accumulate in the liver following APAP intoxication; moreover, Gal-3 plays a role in promoting a persistent proinflammatory macrophage phenotype.

PubMed ID: 23175698

MeSH Terms: Acetaminophen/administration & dosage; Acetaminophen/toxicity*; Analgesics/administration & dosage; Analgesics/toxicity; Animals; Galectin 3/deficiency; Galectin 3/genetics; Galectin 3/physiology*; Immunophenotyping; Inflammation Mediators/toxicity*; Liver/drug effects; Liver/immunology*; Liver/pathology*; Macrophage Activation/drug effects; Macrophage Activation/genetics; Macrophage Activation/immunology*; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Random Allocation