15-Deoxy-Δ 12,14 -Prostaglandin J 2 Exerts Proresolving Effects Through Nuclear Factor E2-Related Factor 2-Induced Expression of CD36 and Heme Oxygenase-1

Aims: 15-Deoxy-(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been shown to rescue cells from inflammatory insults and to participate in the resolution of acute inflammation. In this study, we investigated molecular mechanisms underlying proresolving effects of 15d-PGJ(2). Results: 15d-PGJ(2) injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ(2) administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ(2) increased the proportion of macrophages engulfing apoptotic neutrophils, a process called efferocytosis. In addition, when the thioglycollate-elicited mouse peritoneal macrophages were stimulated with 15d-PGJ(2), their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ(2) conducted phagocytic clearance of apoptotic cells to a greater extent than the control cells. Under these conditions, expression of CD36 and heme oxygenase-1 (HO-1) was enhanced along with increased accumulation of the nuclear factor E2-related factor 2 (Nrf2) in the nucleus. Knockdown of Nrf2 abolished 15d-PGJ(2)-induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ(2)-induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ(2)-induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ(2), its nonelectrophilic analog 9,10-dihydro-15d-PGJ(2) lacking the ,-unsaturated carbonyl group could not induce CD36 expression and efferocytosis. Innovation: 15d-PGJ(2), as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ(2) possesses a therapeutic value in the management of inflammatory disorders. Conclusion: 15d-PGJ(2) facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid.