Potentiation of Efferocytic Activity of Macrophages by 15-Ketoprostaglandin E2

Abstract

Resolution of inflammation is an essential component of orchestrated host defense responses that counterbalances proinflammatory insults to restore homeostasis. One of the key features of resolution is the phagocytic clearance of superfluous cells which is termed efferocytosis. Over the years, researchers have found various endogenous lipid mediators with potential proresolving and anti-inflammatory properties. An example is 15-ketoprostaglandin E2 (15-ketoPGE2) which has recently been shown to modulate activity of some key transcription factors involved in pro- or anti-inflammatory processes. In the present study, I investigated the proresolving activity of 15-ketoPGE2 in a zymosan A-induced mouse peritonitis model. I found that 15-ketoPGE2 treatment enhanced the efferocytic activity of macrophages for the removal of apoptotic neutrophils. 15-KetoPGE2 stimulated expression of T-cell immunoglobulin- and mucin-domain-containing molecule 4 (TIM4), a phosphatidylserine receptor which is known to be involved in pathogen recognition by macrophages. 15-KetoPGE2 also upregulated expression of nuclear factor-erythroid-2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in peritoneal macrophages of zymosan A-treated mice. In another experiment, 15-ketoPGE2 treatment potentiated efferocytic activity of bone marrow-derived macrophages (BMDM) and RAW 264.7 cells co-incubated with apoptotic thymocytes. Notably, 15-ketoPGE2 treatment facilitated degradation of kelch-like ECH-associated protein 1 (Keap1) which accounts for activation of Nrf2 and subsequent upregulation of HO-1 expression in BMDM. 15-KetoPGE2-induced expression of HO-1 in BMDM appears to contribute to upregulation of LC3-II protein. In summary, 15-KetoPGE2 potentiates efferocytic activity of macrophages via the Nrf2/HO-1 axis. The induction of HO-1 upregulates TIM4 receptor and LC3-II protein which facilitates the efferocytosis mediated by macrophages.

Keyword: 15-Ketoprostaglandin E2, Efferocytosis, Nuclear factor-erythroid-2-related factor 2, Heme oxygenase-1, T-cell immunoglobulin- and mucin-domain-containing molecule, LC3-associated phagocytosis.