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Published on: October 21, 2017
MCC950 Ameliorates Acute Liver Injury Through Modulating Macrophage Polarization and Myeloid-Derived Suppressor Cells
Wei Yan1,2, Yingchun Shen3, Jinny Huang2
1Hepatobiliary Center, The First Affiliated Hospital, Nanjing Medical University, Nanjing, China.
Abstract:
Acute liver injury (ALI) raises high mortality rates due to a rapid pathological process. MCC950, a highly selective nod-like receptor family pyrin domain containing 3 (NLRP3) inhibitor, has already been reported to show strong hepatoprotective effects in many different liver diseases. In this study, we unveiled the role of MCC950 in carbon tetrachloride (CCl4)-induced ALI and its underlying molecular mechanisms on days 1, 2, and 3. MCC950 could significantly inhibit liver injury, evidenced by decreased serum alamine aminotransferase (ALT) and aspartate aminotransferase (AST) levels on days 1 and 2, increased Albumin (ALB) level on day 3, and decreased histological score during the whole period. Moreover, lower M1 macrophage related to pro-inflammatory genes expression was observed in MCC950-treated ALI mice on day 1, while MCC950 pretreatment also polarized macrophage to M2 phenotype indicating anti-inflammatory response on days 2 and 3. Additionally, MDSC was significantly increased in blood, liver, and spleen in ALI mice at different time courses. Specifically, upregulated myeloid-derived suppressor cell (MDSC) proportions were found in blood and spleen on days 1 and 2, but showed decreased trend on day 3. However, liver MDSC numbers were increased on days 2 and 3, but no significance on day 1. In conclusion, MCC950 pretreatment alleviates CCl4-induced ALI through enhanced M2 macrophage and MDSC function at different time points of ALI. Further understanding of MCC950 in ALI may be a new potential therapeutic strategy.
Insights
MCC950 effectively treats acute liver injury (ALI) by modulating immune cells. This NLRP3 inhibitor reduces liver damage and inflammation, offering a potential new therapy for ALI.
Area of Science:
- Immunology
- Hepatology
- Pharmacology
Background:
- Acute liver injury (ALI) is a critical condition with high mortality.
- The nod-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a key role in liver injury.
- MCC950 is a selective NLRP3 inhibitor with known hepatoprotective potential.
Purpose of the Study:
- To investigate the therapeutic effects of MCC950 on carbon tetrachloride (CCl4)-induced ALI.
- To elucidate the underlying molecular mechanisms of MCC950 in ALI.
- To analyze the impact of MCC950 on immune cell populations during ALI.
Main Methods:
- Administration of MCC950 to mice with CCl4-induced ALI.
- Assessment of liver injury markers including serum ALT, AST, and albumin levels.
- Histological evaluation of liver tissue.
- Analysis of macrophage polarization (M1/M2) and myeloid-derived suppressor cell (MDSC) populations.
Main Results:
- MCC950 significantly reduced liver injury markers (ALT, AST) and histological damage.
- MCC950 inhibited pro-inflammatory M1 macrophages and promoted anti-inflammatory M2 macrophages.
- MCC950 modulated myeloid-derived suppressor cell (MDSC) levels in blood, spleen, and liver at different time points.
Conclusions:
- MCC950 demonstrates significant hepatoprotective effects in CCl4-induced ALI.
- The therapeutic mechanism involves the modulation of macrophage polarization and MDSC function.
- MCC950 represents a promising therapeutic strategy for managing acute liver injury.
