IFN-\u03b2 is a macrophage-derived effector cytokine facilitating the resolution of bacterial inflammation

Senthil Kumaran Satyanarayanan,Sergei Butenko,János G Filep,Dalit Barkan,Meriem Sekheri,Sagie Schif-Zuck,Janan Saadi,Amiram Ariel,Yonatan Feuermann,Amira Othman,Driss El Kebir,Simaan Assi,Soaad Soboh,Noa Sher,Neta Peled

doi:10.1038/s41467-019-10903-9

Senthil Kumaran Satyanarayanan, Sergei Butenko + Show 13 more

Open Access

https://doi.org/10.1038/s41467-019-10903-9

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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.

Highlights

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation
We found that pretreatment of mice with an anti-IFN-β antibody delayed E. coli clearance at 24 h (Fig. 3a) while enhanced E. coli–evoked edema formation (Fig. 3b, c), lung myeloperoxidase content, an index of neutrophil accumulation (Fig. 3d), Bronchoalveolar lavage (BAL) fluid total leukocyte (Fig. 3e), and PMN (Fig. 3f) and monocyte counts (Fig. 3g) in comparison to IgG controls
We propose that IFN-β mediates both feedback and bidirectional crosstalk between non-phagocytic macrophages, phagocytic macrophages and neutrophils, thereby defining a novel resolution circuit

Summary

Introduction

The uptake of apoptotic polymorphonuclear cells (PMN) by macrophages is critical for timely resolution of inflammation. STAT3 signalling in response to IFN-β promotes apoptosis of human PMNs. uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo. Uptake of apoptotic cells promotes loss of phagocytic capacity in macrophages alongside decreased surface expression of efferocytic receptors in vivo These results identify IFN-β produced by resolution phase macrophages as an effector cytokine in resolving bacterial inflammation. We show that non-phagocytic macrophages are generated exclusively following the uptake of apoptotic cells in an irreversible manner, and this conversion is associated with reduced surface expression of efferocytic receptors. These findings identify IFN-β as a macrophage-derived multi-pronged effector in resolving inflammation

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