Yamate Jyoji, Izawa Takeshi, Kuwamura Mitsuru
Laboratory of Veterinary Pathology, Life and Environmental Sciences, Osaka Prefecture University, Rinkuu Ourai Kita 1-58, Izumisano, Osaka 598-8531, Japan.
Food Saf (Tokyo). 2016 Sep 17;4(3):61-73. doi: 10.14252/foodsafetyfscj.2016012. eCollection 2016 Sep.
Hepatic macrophages play an important role in homeostasis. The functional abnormalities of hepatic macrophages primarily or secondarily influence chemically induced hepatotoxicity. However, the evaluation system based on their functions has not yet been established. Recently, a new concept (M1-/M2-macrophage polarization) was proposed; M1-macropahges are induced by INF-γ, and show high phagocytosis/tissue damage, whereas M2-macropahges are induced by IL-4 and play roles in reparative fibrosis by releasing IL-10 and TGF-β1. In hepatogenesis, CD68-expressing M1-macrophages predominantly exist in embryos; in neonates, in contrast, CD163-/CD204-expressing M2-macrophages appear along the sinusoids and mature as Kupffer cells. Activated Kupffer cells by liposome decrease AST and ALT values, whereas AST and ALT values are increased under Kupffer cells depleted with clodronate treatment. Since Kupffer cells may be involved in clearance of liver enzymes, macrophage condition should be taken into consideration when hepatotoxicity is analyzed. In TAA-induced acute hepatic lesions, INF-γ, TNF-α and IL-6 for M1-factors and IL-4 for M2-factors are already increased before histopathological change; the appearance of CD68-expressing M1-macrophages and CD163-expressing M2-macrophages follows in injured centrilobular lesions, and TGF-β1 and IL-10 are increased for reparative fibrosis. CD68-expressing M1-macrophages co-express MHC class II and Iba-1, whereas CD163-expressing M2-macrophages also express CD204 and Galectin-3. Under macrophage depletion by clodoronate, TAA-treated rat livers show prolonged coagulation necrosis of hepatocytes, and then develop dystrophic calcification without reparative fibrosis. The depletion of hepatic macrophages influences hepatic lesion development. Collectively, a histopathological analysis method for hepatotoxicity according to M1-/M2-macrophage polarization would lead to the refinement of hazard characterization of chemicals in food and feed.
肝巨噬细胞在体内平衡中发挥着重要作用。肝巨噬细胞的功能异常会直接或间接影响化学诱导的肝毒性。然而，基于其功能的评估体系尚未建立。最近，一个新的概念（M1/M2巨噬细胞极化）被提出；M1巨噬细胞由INF-γ诱导，具有高吞噬作用/组织损伤作用，而M2巨噬细胞由IL-4诱导，通过释放IL-10和TGF-β1在修复性纤维化中发挥作用。在肝脏发生过程中，表达CD68的M1巨噬细胞主要存在于胚胎中；相反，在新生儿中，表达CD163/CD204的M2巨噬细胞沿肝血窦出现并发育为库普弗细胞。脂质体激活的库普弗细胞可降低AST和ALT值，而用氯膦酸盐处理使库普弗细胞耗竭时，AST和ALT值会升高。由于库普弗细胞可能参与肝酶的清除，因此在分析肝毒性时应考虑巨噬细胞的状态。在TAA诱导的急性肝损伤中，M1因子INF-γ、TNF-α和IL-6以及M2因子IL-4在组织病理学改变之前就已经升高；表达CD68的M1巨噬细胞和表达CD163的M2巨噬细胞出现在受损的小叶中心病变中，TGF-β1和IL-10升高以促进修复性纤维化。表达CD68的M1巨噬细胞共表达MHC II类分子和Iba-1，而表达CD163的M2巨噬细胞也表达CD204和半乳糖凝集素-3。在氯膦酸盐导致巨噬细胞耗竭的情况下，TAA处理的大鼠肝脏显示肝细胞的凝血性坏死延长，随后发展为营养不良性钙化，且无修复性纤维化。肝巨噬细胞的耗竭会影响肝损伤的发展。总体而言，一种根据M1/M2巨噬细胞极化进行肝毒性组织病理学分析的方法将有助于完善食品和饲料中化学物质的危害特征描述。
