Ly6cLo non-classical monocytes promote resolution of rhesus rotavirus-mediated perinatal hepatic inflammation

Abstract

Perinatal hepatic inflammation can have devastating consequences. Monocytes play an important role in the initiation and resolution of inflammation, and their diverse functions can be attributed to specific cellular subsets: pro-inflammatory or classical monocytes (Ly6c^Hi) and pro-reparative or non-classical monocytes (Ly6c^Lo). We hypothesized that inherent differences in Ly6c^Hi classical monocytes and Ly6c^Lo non-classical monocytes determine susceptibility to perinatal hepatic inflammation in late gestation fetuses and neonates. We found an anti-inflammatory transcriptional profile expressed by Ly6c^Lo non-classical monocytes, and a physiologic abundance of these cells in the late gestation fetal liver. Unlike neonatal pups, late gestation fetuses proved to be resistant to rhesus rotavirus (RRV) mediated liver inflammation. Furthermore, neonatal pups were rendered resistant to RRV-mediated liver injury when Ly6c^Lo non-classical monocytes were expanded. Pharmacologic inhibition of Ly6c^Lo non-classical monocytes in this setting restored susceptibility to RRV-mediated disease. These data demonstrate that Ly6c^Lo monocytes promote resolution of perinatal liver inflammation in the late gestation fetus, where there is a physiologic expansion of non-classical monocytes, and in the neonatal liver upon experimental expansion of these cells. Therapeutic strategies directed towards enhancing Ly6c^Lo non-classical monocyte function may mitigate the detrimental effects of perinatal liver inflammation.