IFNβ is a novel effector cytokine in resolving inflammation and skin fibrosis

The engulfment of apoptotic leukocytes (efferocytosis) by macrophages during the resolution of inflammation is essential for tissue homeostasis and results in macrophage reprogramming/immune-silencing. However, a distinct subset of resolution phase macrophages loss their phagocytic capacity following intense efferocytosis, and hence were termed satiated macrophages. Here, we show using an unbiased RNA-Seq analysis that non-phagocytic macrophages express a distinct IFN-β-related signature. Moreover, we report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates during the resolution of peritonitis and pneumonia in mice, respectively. Elimination of endogenous IFN-β impairs, whereas the treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. Moreover, through STAT3, IFN-β promotes apoptosis of human PMN. Finally, we show exacerbated skin fibrosis in D6/ACKR2-deficient mice is associated with reduced IFN-β levels and can be rescued by exogenous IFN-β. Collectively, our results identify IFN-β produced by resolution phase macrophages as a novel multi-pronged effector cytokine in resolving inflammation and skin fibrosis.