IFN-β and ARTS deficiency promote the generation of hyper-efferocytic Ly6C macrophages in resolving inflammation in male mice.

During the resolution of inflammation, Ly6CF4/80 monocytes differentiate to Ly6CF4/80 macrophages that exert apoptotic cell engulfment (efferocytosis) properties and consequently convert to interferon (IFN)-β-producing macrophages. Here, we report that exposure to IFN-β, or transforming growth factor (TGF)-β, or a deficiency in the pro-apoptotic protein ARTS, results in the conversion of mature macrophages to an Ly6CF4/80CCR2 phenotype in vivo and ex vivo. Deficiency in ARTS or caspase inhibition results in enhanced conversion of macrophages to the Ly6C phenotype. Moreover, IFN-β-triggered Ly6C macrophages are hyper-efferocytic and express higher levels of the efferocytic receptor CD36. Inhibition of CD36 ligation results in complete abrogation of efferocytosis ex vivo in both Ly6C and Ly6C macrophages. Notably, IFN-β also promotes the emergence of Ly6C macrophages during the resolution of liver fibrosis, while transcriptomic analysis further links this rejuvenated phenotype to macrophage subsets found in human inflammatory liver disease. Altogether, our findings indicate IFN-β promotes macrophage conversion to a distinct hyper-efferocytic phenotype that is limited by ARTS and apoptosis during the resolution of inflammation.