17-Oxo-DHA Potentiates Macrophage Efferocytosis via Nrf2/HO-1-Mediated Biosynthesis of Specialized Pro-Resolving Mediators

Phagocytic engulfment of apoptotic cells, particularly neutrophils by macrophages, known as efferocytosis, is crucial in preventing secondary necrosis and promoting tissue repair. 17-Oxo-DHA, an electrophilic metabolite of docosahexaenoic acid (DHA), is generated in macrophages and has been reported to contribute to inflammation resolution by enhancing efferocytosis. However, many gaps remain in our understanding of the pro-resolving effects of 17-oxo-DHA. Our results reveal that 17-oxo-DHA augments the efferocytic activity of bone marrow-derived macrophages (BMDMs) by stimulating the biosynthesis of resolvin D2 (RvD2), one of the prototypic pro-resolving mediators (SPMs), while reducing the expressions of IL-6 and TNF-α. Mechanistically, either gene silencing of Nrf2 or pharmacological inhibition of its target protein HO-1 suppresses 17-oxo-DHA-induced efferocytosis, decreasing the levels of 15-LOX, COX-2, and various SPMs. Notably, treatment of macrophages with SPMs was able to restore 17-oxo-DHA-induced efferocytosis even when HO-1 activity was suppressed. Thus, our study suggests critical roles of SPMs and the Nrf2/HO-1 axis in mediating 17-oxo-DHA-induced efferocytosis, which are novel candidate therapeutic targets in non-resolving inflammatory diseases.