Apoptotic cell-derived metabolites in efferocytosis-mediated resolution of inflammation

The resolution of inflammation, as part of standard host defense mechanism, is the process to guarantee timely termination of inflammatory responses and eventual restoration of tissue homeostasis . It is mainly achieved via efferocytosis, during which pro-resolving macrophages clear apoptotic neutrophils at the inflammatory site. Unfortunately, impaired resolution can be the leading cause of chronic inflammatory disorders and some autoimmune diseases. Existing studies have provided relatively comprehensive understandings about the recognition and uptake of apoptotic neutrophils by macrophages during early phases of efferocytosis. However, lack of information concerns macrophage metabolism of apoptotic cell-derived metabolites after being released from phagolysosomes or the relationship between such metabolism and efferocytosis. Notwithstanding, three recent studies have revealed macrophage metabolism of cholesterol, fatty acids and arginine, as well as their respective functions in the context of inflammation-resolution. This review provides an overview of the resolution of inflammation, efferocytosis and the key players involved, followed by a focus on the metabolism of apoptotic cell-derived metabolites within efferocytes. Hypotheses of more potential apoptotic cell-derived metabolites and their possible roles in the resolution are also formulated. Understanding the effect of these metabolites further advances the concept that apoptotic cells act as active players to regulate resolution, and also suggests novel therapeutic strategies for diseases driven by defective resolution and even cancer that may be treated through enhanced efferocytosis.