Glycyrrhizin Protects γ-Irradiated Mice from Gut Bacteria–Associated Infectious Complications by Improving miR-222–Associated Gas5 RNA Reduction in Macrophages of the Bacterial Translocation Site

Gut bacteria-associated sepsis is a serious concern in patients with gastrointestinal acute radiation syndrome (GIARS). In our previous studies, gut bacteria-associated sepsis caused high mortality rates in mice exposed to 6-9 Gy of gamma-rays. IL-12(+)CD38(+) iNOS(+) Mvarphi (M1Mvarphi) located in the bacterial translocation site (mesenteric lymph nodes [MLNs]) of unirradiated mice were characterized as host defense antibacterial effector cells. However, cells isolated from the MLNs of GIARS mice were mostly CCL1(+)IL-10(+)LIGHT(+)miR-27a(+) Mvarphi (M2bMvarphi, inhibitor cells for the M1Mvarphi polarization). Reduced long noncoding RNA Gas5 and increased miR-222 expression in MLN-Mvarphi influenced by the irradiation were shown to be associated with M2bMvarphi polarization. In this study, the mortality of mice exposed to 7 Gy of gamma-rays (7 Gy GIARS mice) was completely controlled after the administration of glycyrrhizin (GL), a major active ingredient in licorice root (Glycyrrhiza glabra). Bacterial translocation and subsequent sepsis were minimal in 7 Gy GIARS mice treated with GL. Increased Gas5 RNA level and decreased miR-222 expression were shown in MLN-Mvarphi isolated from 7 Gy GIARS mice treated with GL, and these macrophages did not display any properties of M2bMvarphi. These results indicate that gut bacteria-associated sepsis in 7 Gy GIARS mice was controlled by the GL through the inhibition of M2bMvarphi polarization at the bacteria translocation site. Expression of Ccl1, a gene required for M2bMvarphi survival, is silenced in the MLNs of 7 Gy GIARS mice because of Gas5 RNA, which is increased in these cells after the suppression of miR-222 (a Gas5 RNA expression inhibitor) by the GL.