TY - JOUR
T1 - MyD88 in myofibroblasts enhances nonalcoholic fatty liver disease-related hepatocarcinogenesis via promoting macrophage M2 polarization
AU - Liu, Yu
AU - Chen, Haiqiang
AU - Yan, Xuanxuan
AU - Zhang, Jie
AU - Deng, Zhenzhong
AU - Huang, Maosheng
AU - Gu, Jianchun
AU - Zhang, Jinhua
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown. Results: Myofibroblast MyD88-deficient (SMAMyD88−/−) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on the CCR1 receptor and STAT6/ PPARβ pathway. Furthermore, liver tumor growth was attenuated in mice treated with a CCR1 inhibitor. CCLl5 (homologous protein CCL9 in humans) expression was increased in myofibroblasts of HCC and was associated with shorter survival of patients with HCC. Thus, our results indicate that MyD88 in myofibroblasts promotes NAFLD-related HCC progression and may be a promising therapeutic target for HCC treatment. Conclusion: This study demonstrates that MyD88 in myofibroblasts can promote nonalcoholic fatty liver disease-related hepatocarcinogenesis by enhancing macrophage M2 polarization, which might provide a potential molecular therapeutic target for HCC. Graphical Abstract: [Figure not available: see fulltext.]
AB - Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of chronic liver diseases and has emerged as the leading factor in the pathogenesis of hepatocellular carcinoma (HCC). MyD88 contributes to the development of HCC. However, the underlying mechanism by which MyD88 in myofibroblasts regulates NAFLD-associated liver cancer development remains unknown. Results: Myofibroblast MyD88-deficient (SMAMyD88−/−) mice were protected from diet-induced obesity and developed fewer and smaller liver tumors. MyD88 deficiency in myofibroblasts attenuated macrophage M2 polarization and fat accumulation in HCC tissues. Mechanistically, MyD88 signaling in myofibroblasts enhanced CCL9 secretion, thereby promoting macrophage M2 polarization. This process may depend on the CCR1 receptor and STAT6/ PPARβ pathway. Furthermore, liver tumor growth was attenuated in mice treated with a CCR1 inhibitor. CCLl5 (homologous protein CCL9 in humans) expression was increased in myofibroblasts of HCC and was associated with shorter survival of patients with HCC. Thus, our results indicate that MyD88 in myofibroblasts promotes NAFLD-related HCC progression and may be a promising therapeutic target for HCC treatment. Conclusion: This study demonstrates that MyD88 in myofibroblasts can promote nonalcoholic fatty liver disease-related hepatocarcinogenesis by enhancing macrophage M2 polarization, which might provide a potential molecular therapeutic target for HCC. Graphical Abstract: [Figure not available: see fulltext.]
KW - CCL9/CCL15
KW - Hepatocellular carcinoma
KW - Macrophage polarization
KW - MyD88
KW - Nonalcoholic fatty liver disease
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U2 - 10.1186/s12964-024-01489-x
DO - 10.1186/s12964-024-01489-x
M3 - Article
C2 - 38291436
AN - SCOPUS:85183641287
SN - 1478-811X
VL - 22
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
IS - 1
M1 - 86
ER -