Abstract B72: Resolvin D1, derived from n-3 polyunsaturated fatty acid, stimulates efferocytosis and protects macrophages from oxidative stress-induced apoptosis

Abstract

Abstract 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 (DHA)-derived resolvin D1 (RvD1), endogenously generated during resolution of inflammation, is known to stimulate efferocytosis, but little is known about the mechanism of its action. In the present study, we found that lipopolysaccharide (LPS; 200 g/ml) suppressed efferocytosis by murine macrophage-like RAW264.7 cells, and RvD1 (50 nM) restored the phagocytic ability of these cells by down-regulating TNF-α expression. The inhibitory effect of RvD1 on LPS-induced TNF-α expression was associated with enhanced nuclear localization of p50/p50 homodimer and concomitant reduction in the nuclear levels of p65/p50 heterodimer. siRNA knockdown of NF-κB p50 abolished RvD1-mediated suppression of TNF-α expression and resulted in impaired efferocytosis, suggesting that the replacement of p65/p50 with p50/p50 homodimer is an essential event for RvD1-mediated stimulation of efferocytosis. In a murine peritonitis model, intraperitoneal administration of RvD1 (300 ng) abrogated zymosan A (30 mg/kg)-induced TNF-α production, thereby reactivating efferocytosis. In addition, RvD1 protected RAW264.7 cells from oxidative stress-induced apoptosis during efferocytosis. The generation of reactive oxygen species after efferocytosis was markedly blocked in RvD1-exposed macrophages. Moreover, RvD1 upregulated the anti-apoptotic Bcl-2 and Bcl-xL expression and downregulated the proapoptotic Bax and Bad expression. In conclusion, RvD1 expedites resolution of inflammation through stimulating efferocytosis while preserving viability of macrophage during efferocytosis. These findings account, at least in part, for the chemopreventive effects of DHA on inflammation-associated carcinogenesis. Citation Information: Cancer Prev Res 2011;4(10 Suppl):B72.