IL-4 treatment induces apoptosis of blood monocytes and proliferation of recruited injury-associated macrophages to resolve liver injury

IL-4 can have significant therapeutic benefit in many injury settings, but its mechanism of action is unclear. Using a model of carbon tetrachloride (CCl₄)-mediated acute liver injury, we find that exogenous IL-4 causes a dramatic shift from recruited Ly6C^hi monocytes to an abundance of monocyte-derived macrophages (MoMFs) within the injured tissue that is accompanied by reduced indices of hepatic damage and enhanced hepatic regeneration. Rather than altering the recruitment or differentiation of monocytes, treatment with IL-4 triggers monocyte apoptosis alongside proliferation of MoMFs. Single-cell RNA sequencing reveals injury and cell-type-specific responses to IL-4 treatment across hepatic myeloid lineages and a largely pro-reparative gene signature in the expanded pool of MoMFs. IL-4 treatment fails to enhance hepatic repair when the accrual of MoMFs is limited using Ccr2-deficient monocytopenic mice. Together, these data reveal a pathway through which therapeutic IL-4 alters the composition, number, and function of injury-associated myeloid cells to resolve liver injury.