IFN-β exposure and ARTS deficiency promote the generation of hyper-efferocytic Ly-6C⁺ macrophages during the resolution of inflammation

During the resolution of inflammation, Ly-6C⁺F4/80^- monocytes differentiate to Ly-6C^-F4/80⁺ macrophages that exert efferocytic properties and consequently convert to IFN-β-producing macrophages. Here, we report that exposure to IFN-β, or TGF-β, or a deficiency in the pro-apoptotic protein ARTS, results in the conversion of mature macrophages to a rejuvenated Ly-6C⁺F4/80⁺CCR2⁺ phenotype. This phenotype appeared only in peritoneal resolution phase macrophages and not in their splenic or bone marrow counterparts or unchallenged peritoneal macrophages. Moreover, IFN-β-triggered rejuvenated macrophages were hyper-efferocytic and expressed higher levels of the efferocytic receptor CD36. Inhibition of CD36 ligation resulted in complete abrogation of efferocytosis ex vivo in both mature and rejuvenated macrophages. Altogether, our findings indicate an unprecedented phenomenon in which IFN-β promotes macrophage rejuvenation and efferocytosis that are limited by ARTS-mediated apoptosis during the resolution of inflammation.