Wonki Kim1, Ha-Na Lee1, Jeong-Hoon Jang1, Seung Hyeon Kim1, Yeon-Hwa Lee1, Young-Il Hahn1, Hoang-Kieu-Chi Ngo1, Yeonseo Choi1, Yeonsoo Joe2, Hun Taeg Chung2, Yingqing Chen2, Young Nam Cha3, Young-Joon Surh1,4,5. 1. 1 Tumor Microenvironment Global Core Research Center and Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University , Seoul, Republic of Korea. 2. 2 School of Biological Sciences, University of Ulsan , Meta-Inflammation Basic Research Laboratory, Ulsan, Republic of Korea. 3. 3 Department of Pharmacology and Toxicology, College of Medicine, Inha University , Incheon, Republic of Korea. 4. 4 Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science, Seoul National University , Seoul, Republic of Korea. 5. 5 Cancer Research Institute, Seoul National University , Seoul, Republic of Korea.
Abstract
AIMS: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) 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-PGJ2. RESULTS: 15d-PGJ2 injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ2 administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ2 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-PGJ2, their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ2 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-PGJ2-induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ2-induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ2-induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ2, its nonelectrophilic analog 9,10-dihydro-15d-PGJ2 lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis. INNOVATION: 15d-PGJ2, as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ2 possesses a therapeutic value in the management of inflammatory disorders. CONCLUSION: 15d-PGJ2 facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.
AIMS: 15-Deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) 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-PGJ2. RESULTS:15d-PGJ2 injected into the peritoneum of mice facilitated the resolution of zymosan A-induced peritonitis. 15d-PGJ2 administration reduced the number of total leukocytes and attenuated polymorphonuclear leukocyte infiltration. Furthermore, 15d-PGJ2 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-PGJ2, their efferocytic activity was amplified. In another experiment, RAW264.7 murine macrophages exposed to 15d-PGJ2 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-PGJ2-induced expression of CD36 and HO-1, and silencing of CD36 and HO-1 attenuated 15d-PGJ2-induced efferocytosis. Moreover, peritoneal macrophages isolated from Nrf2-null mice failed to upregulate 15d-PGJ2-induced expression of CD36 and HO-1 and to mediate efferocytosis. Unlike 15d-PGJ2, its nonelectrophilic analog 9,10-dihydro-15d-PGJ2 lacking the α,β-unsaturated carbonyl group could not induce CD36 expression and efferocytosis. INNOVATION: 15d-PGJ2, as one of the terminal products of cyclooxygenase-2, exerts proresolving effects through induction of efferocytosis. The results of this study suggest that 15d-PGJ2 possesses a therapeutic value in the management of inflammatory disorders. CONCLUSION:15d-PGJ2 facilitates resolution of inflammation by inducing Nrf2-induced expression of CD36 and HO-1 in macrophages. Antioxid. Redox Signal. 27, 1412-1431.
Entities:
Keywords:
15-deoxy-Δ12,14-prostaglandin J2; Nrf2; efferocytosis; heme oxygenase-1; resolution of inflammation
Authors: Alicia R Mathers; Cara D Carey; Meaghan E Killeen; Sonia R Salvatore; Laura K Ferris; Bruce A Freeman; Francisco J Schopfer; Louis D Falo Journal: Free Radic Biol Med Date: 2017-11-10 Impact factor: 7.376
Authors: Manuel U Ramirez; Elizabeth R Stirling; Nancy J Emenaker; David D Roberts; David R Soto-Pantoja Journal: Cancer Metastasis Rev Date: 2018-09 Impact factor: 9.264
Authors: Ulrike Baschant; Jan P Tuckermann; Mascha Koenen; Stephan Culemann; Sabine Vettorazzi; Giorgio Caratti; Lucien Frappart; Wolfgang Baum; Gerhard Krönke Journal: Ann Rheum Dis Date: 2018-07-11 Impact factor: 19.103
Authors: Larissa Staurengo-Ferrari; Stephanie Badaro-Garcia; Miriam S N Hohmann; Marília F Manchope; Tiago H Zaninelli; Rubia Casagrande; Waldiceu A Verri Journal: Front Pharmacol Date: 2019-01-11 Impact factor: 5.810
Authors: Doumet Georges Helou; Stefan F Martin; Marc Pallardy; Sylvie Chollet-Martin; Saadia Kerdine-Römer Journal: Front Immunol Date: 2019-05-07 Impact factor: 7.561
Authors: Kenji W Ruiz-Miyazawa; Larissa Staurengo-Ferrari; Felipe A Pinho-Ribeiro; Victor Fattori; Tiago H Zaninelli; Stephanie Badaro-Garcia; Sergio M Borghi; Ketlem C Andrade; Juliana T Clemente-Napimoga; Jose C Alves-Filho; Thiago M Cunha; Leonardo F Fraceto; Fernando Q Cunha; Marcelo H Napimoga; Rubia Casagrande; Waldiceu A Verri Journal: Sci Rep Date: 2018-09-18 Impact factor: 4.379
Authors: Hee Jin Son; Nayoung Kim; Chin-Hee Song; Sun Min Lee; Ha-Na Lee; Young-Joon Surh Journal: Korean J Intern Med Date: 2018-10-22 Impact factor: 2.884