IFN-β is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation

Abstract

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. High-burden uptake of apoptotic cells is associated with loss of phagocytosis in resolution phase macrophages. Here, using a transcriptomic analysis of macrophage subsets, we show that non-phagocytic resolution phase macrophages express a distinct IFN-β-related gene signature in mice. We also report elevated levels of IFN-β in peritoneal and broncho-alveolar exudates in mice during the resolution of peritonitis and pneumonia, respectively. Elimination of endogenous IFN-β impairs, whereas treatment with exogenous IFN-β enhances, bacterial clearance, PMN apoptosis, efferocytosis and macrophage reprogramming. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. Finally, uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Collectively, these results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation.

Transcriptomic Analysis of Monocyte-Derived Non-Phagocytic Macrophages Favors a Role in Limiting Tissue Repair and Fibrosis

“…CD11b low macrophages migrate out of inflamed sites and, compared to CD11b high cells, exert decreased phagocytic activity despite containing higher numbers of PMNs previously engulfed. Hence, they were termed satiated or non-phagocytic macrophages (17,18). A similar series of phenotypic transitions by monocyte-derived macrophages was previously reported in acute liver injury, where Ly6C hi monocytes infiltrate the liver, clear apoptotic neutrophils, and convert to Ly6C lo macrophages that express 12/15-LO (19)(20)(21).…”

“…RNA extraction was performed as previously described (17). Briefly, all RNA species from sorted cells were extracted using the Aurum Total RNA kit (Bio-Rad Laboratories, Inc.).…”

“…Ly6C + F4/80 − monocytes infiltrate the peritoneal cavity during the onset of resolution (12-24 h post peritonitis) and differentiate gradually to Ly6C − F4/80 hi macrophages that are highly phagocytic/efferocytic (17,28). These phagocytic peritoneal macrophages express high levels of the macrophage surface marker CD11b, in addition to high F4/80.…”

“…This phenotype conversion is accompanied by a reprogramming process and a reduction in both aforementioned surface markers (18). Recently, it was shown that non-phagocytic F4/80 + macrophages express high levels of IFNβ that upon secretion promotes bacterial clearance and the resolution of inflammation (17). IFNβ expression by resolution phase macrophages was also upregulated by the uptake of apoptotic cells (17).…”

“…Recently, IFNβ expression by non-phagocytic macrophages, and the novel roles of this cytokine as an effector in resolving bacterial inflammation were reported (17). We aimed to identify the satiated macrophage subset within the non-phagocytic macrophage population, determine the transcriptomic origin of resolution phase macrophages (of both the phagocytic and non-phagocytic phenotypes), and identify the unique gene clusters expressed by non-phagocytic/satiated macrophages.…”