抄録
Phagocytosis of apoptotic neutrophils by macrophages, called efferocytosis, is critical to resolution of inflammation as this process prevents the exposure of surrounding tissues at the inflammatory site to the toxic contents of lytic cells. Docosahexaenoic acid-derived resolvin D1 (RvD1), endogenously generated during resolution of inflammation, is known to stimulate efferocytosis. However, little is known about the mechanism of RvD1-mediated enhancement of efferocytosis. In the present study, we found that murine macrophage-like RAW264.7 cells treated with lipopolysaccharide (LPS) had markedly decreased efferocytic activity, but the incubation with RvD1 restored the efferocytic ability of the LPS-treated RAW264.7 cells. RvD1 restored the efferocytic activity by down-regulating the LPS-induced upregulation of TNF-α. The inhibitory effect of RvD1 on LPS-induced TNF-α expression was associated with enhanced nuclear localization of p50/p50 homodimer and concomitant reduction of p65/p50 heterodimer in the nucleus. RvD1 triggered extracellular signal-regulated kinase (ERK)-mediated degradation of nuclear factor κB1 (NF-κB1) p105 to generate p50, which was subsequently translocated to the nucleus as p50/p50 homodimer. Knockdown of NF-κB p50 abolished the ability of RvD1 to suppress TNF-α expression and also to restore efferocytosis, suggesting that the replacement of p65/p50 with p50/p50 homodimer in the nucleus is an essential event for RvD1-mediated stimulation of efferocytosis. In a murine peritonitis model, intraperitoneal administration of RvD1 abrogated the zymosan A-induced TNF-α production, thereby stimulating efferocytosis. Taken together, these findings indicate that RvD1 expedites the resolution of inflammation through induction of efferocytosis by p50/p50 homodimer-mediated repression of TNF-α.
