Granulocytic MDSC with Deficient CCR5 Alleviates Lipogenesis and Inflammation in Nonalcoholic Fatty Liver Disease
Autor: | Tzu-Chieh Liao, Jiung-Pang Huang, Yu-Ting Tsai, Wei-Ching Shih, Chi-Chang Juan, Po-Shiuan Hsieh, Li-Man Hung, Chao-Lan Yu |
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Jazyk: | angličtina |
Rok vydání: | 2022 |
Předmět: |
Inflammation
Myeloid-Derived Suppressor Cells Lipogenesis Organic Chemistry General Medicine Catalysis Computer Science Applications Inorganic Chemistry Mice Inbred C57BL Mice Liver Non-alcoholic Fatty Liver Disease Hepatocytes Animals Physical and Theoretical Chemistry CCR5 g-MDSC NAFLD STAT3 lipid metabolism inflammation Molecular Biology Spectroscopy |
Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 21; Pages: 13048 |
ISSN: | 1422-0067 |
DOI: | 10.3390/ijms232113048 |
Popis: | C-C chemokine receptor type 5 (CCR5) positively contributes to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a common metabolic liver disease associated with chronic inflammation. CCR5 signaling also facilitates the immunosuppressive activity of a group of immature myeloid cells known as granulocytic myeloid-derived suppressor cells (g-MDSCs). While both hepatocyte and g-MDSC express CCR5, how CCR5 coordinates these two distinct cell types in the hepatic microenvironment remains largely unknown. Here, we used in vivo and ex vivo approaches to define the molecular details of how CCR5 mediates the crosstalk between hepatocytes and g-MDSCs in a mouse model of NAFLD. Global CCR5-deficient mice exhibited more severe steatosis, increased hepatic gene expression of lipogenesis, and exacerbated liver damage in diet-induced obesity. Either NAFLD or CCR5-deficiency per se is causative for the increase of g-MDSCs. Purified g-MDSCs have a higher survival rate in the fatty liver microenvironment, and blockade of CCR5 significantly decreases g-MDSCs’ expression of anti-inflammatory factors. On the other hand, the null of CCR5 signaling increases hepatocytes’ expression of lipogenic genes in the NAFLD microenvironment. Most importantly, inhibiting g-MDSCs’ CCR5 signaling in the fatty liver microenvironment dramatically reduces STAT3 signaling, lipogenic, and pro-inflammatory gene expression in primary hepatocytes. Adoptive cell transfer experiments further demonstrate that CCR5-deficient g-MDSCs mitigate hepatic lipogenic gene expression without facilitating pro-inflammatory cytokine production and liver damage in NAFLD mice. These results suggest that targeting g-MDSCs’ CCR5 signaling might serve as a potential therapeutic strategy for NAFLD. |
Databáze: | OpenAIRE |
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