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

15-Deoxy-Δ -prostaglandin J (15d-PGJ ) 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 . 15d-PGJ injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ 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 , their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ 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 -induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ -induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ -induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ , its nonelectrophilic analog 9,10-dihydro-15d-PGJ lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis. 15d-PGJ , 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 possesses a therapeutic value in the management of inflammatory disorders. 15d-PGJ facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.