M1- and M2-macrophage polarization in thioacetamide (TAA)-induced rat liver lesions; a possible analysis for hepato-pathology

Abstract

“Classically activated macrophages (M1)” and “alternatively activated macrophages (M2)”, which appear in injured tissues, control either inflammation or remodeling. The mechanism remains unclear. To clarify the M1-/M2-macrophage polarization in acute liver injury, M1- and M2-related factors were analysed in F344 rats by a single injection of TAA (300 mg/kg BW), and liver samples were collected on post injection (PI) hour 10 and days 1 to 10. Macrophage immunopheno-types were analyzed by single and double immuno-labeling. M1-/M2-related factors were analyzed by real-time RT-PCR. On PI hour 10 (when centrilobular lesions were not still developed), expressions of IFN-γ, TNF-α, IL-1ß, and IL-6 for M1, and IL-4 for M2 were already increased, followed by increased expressions of IL-10 and TGF-ß1 for M2 on PI days 1-3 with development of centrilobular lesions and subsequent reparative fibrosis. On PI hour 10, CD204+ and MHC class II+ macrophages already increased in the intact periportal/Glisson’s sheath regions, accompanied by an increased number of granzyme B+ NK cells. Reactive cells at PI hour 10 might produce M1-related factors. In addition to these macrophages, CD68+ and CD163+ macrophages, and CD3+ T cells appeared in the injured centrilobular region on PI days 1-3; there were macrophages reacting simultaneously to CD68/MHC class II, CD163/MHC class II, CD68/CD204, CD163/CD204, and MHC class II/CD204 in varying degrees. Although CD68+ and CD163+ macrophages are regarded as M1- and M2-types, respectively, the double labeling indicated that macrophage immunophenotypes are interchangeable in injured regions and subsequent fibrosis. An M1-/M2-macrophage paradigm would be useful to analyze hepatotoxicity and to understand the pathogenesis. Histol Histopathol 29, 497-511 (2014)