PPAR-gamma activation is associated with reduced liver ischemia-reperfusion injury and altered tissue-resident macrophages polarization in a mouse model

Background PPAR-gamma (gamma) is highly expressed in macrophages and its activation affects their polarization. The effect of PPAR-gamma activation on Kupffer cells (KCs) and liver ischemia-reperfusion injury (IRI) has not yet been evaluated. We investigated the effect of PPAR-gamma activation on KC-polarization and IRI. Materials and methods Seventy percent (70%) liver ischemia was induced for 60mins. PPAR-gamma-agonist or vehicle was administrated before reperfusion. PPAR-gamma-antagonist was used to block PPAR-gamma activation. Liver injury, necrosis, and apoptosis were assessed post-reperfusion. Flow-cytometry determined KC-phenotypes (pro-inflammatory Nitric Oxide +, anti-inflammatory CD206+ and anti-inflammatory IL-10+). Results Liver injury assessed by serum AST was significantly decreased in PPAR-gamma-agonist versus control group at all time points post reperfusion (1hr: 3092 +/- 105 vs 4469 +/- 551; p = 0.042; 6hr: 7041 +/- 1160 vs 12193 +/- 1143; p = 0.015; 12hr: 5746 +/- 328 vs 8608 +/- 1259; p = 0.049). Furthermore, liver apoptosis measured by TUNEL-staining was significantly reduced in PPAR-gamma-agonist versus control group post reperfusion (1hr:2.46 +/- 0.49 vs 6.90 +/- 0.85%;p = 0.001; 6hr:26.40 +/- 2.93 vs 50.13 +/- 8.29%; p = 0.048). H&E staining demonstrated less necrosis in PPAR-gamma-agonist versus control group (24hr:26.66 +/- 4.78 vs 45.62 +/- 4.57%; p = 0.032). The percentage of pro-inflammatory NO+KCs was significantly lower at all post reperfusion time points in the PPAR-gamma-agonist versus control group (1hr:28.49 +/- 4.99 vs 53.54 +/- 9.15%; p = 0.040; 6hr5.51 +/- 0.54 vs 31.12 +/- 9.58%; p = 0.009; 24hr4.15 +/- 1.50 vs 17.10 +/- 4.77%; p = 0.043). In contrast, percentage of anti-inflammatory CD206+ KCs was significantly higher in PPAR-gamma-agonist versus control group prior to IRI (8.62 +/- 0.96 vs 4.88 +/- 0.50%; p = 0.04). Administration of PPAR-gamma-antagonist reversed the beneficial effects on AST, apoptosis, and pro-inflammatory NO+KCs. Conclusion PPAR-gamma activation reduces IRI and decreases the pro-inflammatory NO+ Kupffer cells. PPAR-gamma activation can become an important tool to improve outcomes in liver surgery through decreasing the pro-inflammatory phenotype of KCs and IRI.