The relative abundance of monocyte subsets determines susceptibility to perinatal hepatic inflammation.

Abstract

The devastating consequences of perinatal liver inflammation contribute to a pressing need to develop therapeutics for the diseases that underly this condition. Biliary atresia (BA) is a perinatal inflammatory disease of the liver that results in obliterative cholangiopathy and rapidly progresses to liver failure, requiring transplantation. The ability to develop targeted therapies requires an understanding of the immune mechanisms that mitigate perinatal liver inflammation. This article reviews our recent findings demonstrating that in a murine model of perinatal hepatic inflammation, Ly6cLo non-classical monocytes express a pro-reparative transcriptomic profile and that the relative abundance of Ly6cLo monocytes promotes resolution of perinatal liver inflammation, rendering neonatal pups resistant to disease. We also examine the lineage relationship between monocyte subsets, reviewing data that suggests classical monocytes are a precursor for non-classical monocytes, and the alternative possibility that separate progenitors exist for each subset. Although a precursor-product relationship between classical and non-classical monocytes might exist in certain environments, we argue that they may also arise from separate progenitors, which is evident by sustained Ly6cLo non-classical monocyte expansion when Ly6cHi monocytes are absent. An improved understanding of monocyte subsets and their developmental trajectories during perinatal hepatic inflammation will provide insight into how therapies directed at controlling monocyte function may help alleviate the devastating consequences of diseases like BA.