Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ 08854, USA.
J Immunol. 2012 Dec 15;189(12):5934-41. doi: 10.4049/jimmunol.1201851. Epub 2012 Nov 21.
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.
炎症巨噬细胞被认为与镇痛药对乙酰氨基酚（APAP）引起的肝毒性有关。在这些研究中，我们描述了 APAP 中毒后在肝脏中积累的巨噬细胞的表型，并评估了半乳糖凝集素-3（Gal-3）在巨噬细胞激活中的作用。给野生型小鼠腹腔注射 APAP（300mg/kg）会导致肝脏中出现两种不同的 CD11b（+）细胞亚群，这些细胞表达高水平的单核细胞/巨噬细胞激活标志物 Ly6C。虽然 CD11b（+）/Ly6C（hi）巨噬细胞表现出具有增加的 TNF-α、诱导型一氧化氮合酶和 CCR2 表达的经典激活的促炎表型，但 CD11b（+）/Ly6C（lo）巨噬细胞被替代激活，表达高水平的抗炎细胞因子 IL-10。APAP 中毒也与肝脏中 Gal-3（+）巨噬细胞的积累有关；这些细胞中的大多数是 Ly6C（hi）。Gal-3（-/-）小鼠中 APAP 诱导的 CD11b（+）/Ly6C（hi）巨噬细胞增加明显减少。这种减少在 APAP 后 72 小时明显，与经典巨噬细胞激活标志物诱导型一氧化氮合酶、IL-12 和 TNF-α以及促炎趋化因子 CCL2 和 CCL3 和趋化因子受体 CCR1 和 CCR2 的表达降低相关。相反，APAP 处理的 Gal-3（-/-）小鼠肝脏中 CD11b（+）/Ly6C（lo）巨噬细胞的数量增加；这与替代激活标志物 Ym1 和 Fizz1 的表达增加、肝脏修复增加和肝毒性降低有关。这些数据表明，在 APAP 中毒后，经典和替代激活的巨噬细胞都会在肝脏中积累；此外，Gal-3 在促进持续的促炎巨噬细胞表型中起作用。
