IL-4 treatment induces apoptosis of blood monocytes and proliferation of reparative macrophages to resolve liver injury.
IL-4 can have significant therapeutic benefit in many injury settings, but its mechanism of action is unclear. Here, we show that, in a model ofCCl4-mediatedacuteliver injury, exogenous IL-4 caused adramatic shift from recruited Ly6Chimonocytes to an abundance of monocyte-derived macrophages. This shift in macrophage dynamics was associated with accelerated clearance of necrotic tissue and enhanced hepatocyte regeneration that required IL-4 receptor-signalling to leukocytes. IL-4 did not alter monocyte recruitment or differentiation but instead stimulated monocyte apoptosis and acted on previously-recruited macrophages to drive proliferation and pro-repair characteristics, including expression of key genes involved in dismantling necrotic tissue. Further scRNA-seq analysis of the impact of IL-4 on all hepatic myeloid lineages revealed injury and cell-type specific responses. Together, our data reveal a novel pathway by which IL-4 alters the composition and functional specification of injury-associated myeloid cells and resolves injury in the liver. Overall design: To examine the effect of IL-4 treatment on the composition and activation state of hepatic myloid cells and whether this differs in healthy or  injured liver, we performed scRNAseq on CD45+CD19-CD3-CD31-NK1.1- liver leukocytes from naive mice 48hrs after injection of IL-4c or PBS, or from mice given CCl4-mediated liver injury followed by IL-4c or PBS 24 hrs later, and cells harvested after a further 48 hours.