International immunopharmacology · 2025
MBD2 deficiency attenuates CCl4-induced hepatic fibrosis by inhibiting M2 macrophage polarization.
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Yu Wen, Li Ruihua, Wang Yixian, Wang Ya-Nan, Huang Yaxuan, Zhang Yanxiang, Nie Hao, Liu Lian, Chen Hui, Zheng Bing, Gong Quan
Аннотация
PURPOSE: Methyl-CpG-binding domain protein 2 (MBD2) serves as a pivotal reader of DNA methylation and has been linked to fibrosis in the kidney and lung. However, its role and the underlying mechanisms in liver fibrosis remain unclear.
MATERIALS AND METHODS: Hepatic fibrosis (HF) was induced in C57BL/6 mice using carbon tetrachloride (CCl4). Liver tissues were examined for MBD2 and α-smooth muscle actin (α-SMA) expression at 1, 3, and 5 weeks post-induction. Immunofluorescence analysis was used to detect MBD2 and the macrophage marker F4/80 in liver tissues. To dissect the role of MBD2 in the pathogenesis of HF, a macrophage-specific MBD2 knockout (KO) mouse and their littermates were challenged with CCl4 for 5 weeks. Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) were measured. Liver tissue sections were stained with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red for histopathological examination. Expression of fibrosis-specific proteins, including hydroxyproline (Hyp), α-SMA, and collagen type I (col-1), was assessed. Expression of M2 macrophage markers arginase-1 (Arg-1), YM1, and found in inflammatory zone 1 (FIZZ1), as well as the M1 macrophage marker inducible nitric oxide synthase (iNOS), was evaluated. For in vitro analysis, peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs) from MBD2 KO mice and control littermates were extracted. Macrophage polarization was induced using interleukin-4 (IL-4) to assess the expression of Arg-1, YM1, and FIZZ1.
RESULTS: MBD2 protein expression was found to be significantly increased during HF progression. MBD2 deficiency in macrophages led to reduced serum ALT and AST levels, decreased hepatic tissue damage, lower hepatic Hyp content, and reduced expression of α-SMA and col-1 compared to the control group. Expression of M2 macrophage markers Arg-1, YM1, and FIZZ1 in liver tissues was lower in the MBD2-deficient group, consistent with the results of in vitro macrophage polarization assays. However, there was no significant difference in iNOS expression.
CONCLUSION: The study demonstrates that macrophage-specific MBD2 deletion inhibits M2 macrophage polarization and ameliorates CCl4-induced HF in mice.
MATERIALS AND METHODS: Hepatic fibrosis (HF) was induced in C57BL/6 mice using carbon tetrachloride (CCl4). Liver tissues were examined for MBD2 and α-smooth muscle actin (α-SMA) expression at 1, 3, and 5 weeks post-induction. Immunofluorescence analysis was used to detect MBD2 and the macrophage marker F4/80 in liver tissues. To dissect the role of MBD2 in the pathogenesis of HF, a macrophage-specific MBD2 knockout (KO) mouse and their littermates were challenged with CCl4 for 5 weeks. Serum levels of alanine transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) were measured. Liver tissue sections were stained with hematoxylin and eosin (H&E), Masson's trichrome, and Sirius red for histopathological examination. Expression of fibrosis-specific proteins, including hydroxyproline (Hyp), α-SMA, and collagen type I (col-1), was assessed. Expression of M2 macrophage markers arginase-1 (Arg-1), YM1, and found in inflammatory zone 1 (FIZZ1), as well as the M1 macrophage marker inducible nitric oxide synthase (iNOS), was evaluated. For in vitro analysis, peritoneal macrophages (PMs) and bone marrow-derived macrophages (BMDMs) from MBD2 KO mice and control littermates were extracted. Macrophage polarization was induced using interleukin-4 (IL-4) to assess the expression of Arg-1, YM1, and FIZZ1.
RESULTS: MBD2 protein expression was found to be significantly increased during HF progression. MBD2 deficiency in macrophages led to reduced serum ALT and AST levels, decreased hepatic tissue damage, lower hepatic Hyp content, and reduced expression of α-SMA and col-1 compared to the control group. Expression of M2 macrophage markers Arg-1, YM1, and FIZZ1 in liver tissues was lower in the MBD2-deficient group, consistent with the results of in vitro macrophage polarization assays. However, there was no significant difference in iNOS expression.
CONCLUSION: The study demonstrates that macrophage-specific MBD2 deletion inhibits M2 macrophage polarization and ameliorates CCl4-induced HF in mice.