Gut-Derived Exosomes Induce Liver Injury After Intestinal Ischemia/Reperfusion by Promoting Hepatic Macrophage Polarization

Liver injury induced by intestinal ischemia/reperfusion (I/R) is accompanied by the polarization of Kupffer cells, which are specialized macrophages located in the liver. However, the causes of hepatic macrophage polarization after intestinal I/R remain unknown. This study investigated whether gut-derived exosomes contribute to the pathogenesis of liver injury triggered by intestinal I/R in a murine model and explored the underlying mechanisms. Intestinal I/R models were established by temporally clamping the superior mesenteric arteries of mice. Exosomes were isolated from the intestinal tissue of mice that underwent intestinal I/R or sham surgery according to a centrifugation-based protocol. Exosomes were co-cultured with RAW 264.7 macrophages or injected intravenously in mice. Liposomal clodronate was administered intraperitoneally to deplete the macrophages. Macrophage polarization was determined by flow cytometry, immunohistochemistry, and quantitative polymerase chain reaction. Liver injury was assessed by histological morphology and increased serum aspartate aminotransferase and alanine aminotransferase levels. Exosomes from mice intestines subjected to I/R (IR-Exo) promoted macrophage activation in vitro. Intravenous injection of IR-Exo caused hepatic M1 macrophage polarization and led to liver injury in mice. Depleting macrophages ameliorated liver injury caused by intestinal I/R or the injection of IR-Exo. Furthermore, inhibiting exosome release improved intestinal injury, liver function, and survival rates of mice subjected to intestinal I/R. Our study provides evidence that gut-derived exosomes induce liver injury after intestinal I/R by promoting hepatic M1 macrophage polarization. Inhibition of exosome secretion could be a therapeutic target for preventing hepatic impairment after intestinal I/R.