Resveratrol attenuates LPS/CSE-induced macrophage ferroptosis through activation of the Nrf2-ferroportin axis

BACKGROUND: Resveratrol (Res) has therapeutic effects in a mouse model with chronic obstructive pulmonary disease (COPD). However, the role of ferroportin (FPN) in the Res-mediated therapeutic effects remains unclear. PURPOSE: We investigated the role and signaling pathways of FPN in macrophages and a mouse model with acute exacerbation of COPD (AECOPD) after Res treatment. STUDY DESIGN/METHODS: Res was intraperitoneal (i.p.) injected into AECOPD-like mouse model or added into cultured macrophages prior to LPS/CSE treatment. Macrophages with FPN knockdown and over-expression were established by infection of the cells with lentiviral vector encoding FPN shRNA and cDNA. RESULTS: Res i.p. suppressed pulmonary infiltration of neutrophils and emphysema in the LPS/CSE-treated mice, in association with upregulated expression of FPN. LPS, CSE and their mixture increased the expression of FPN, TNF-α and IL-6 in macrophages, with increased hemosiderin deposits, reactive oxygen species (ROS) and malondialdehyde (MDA), but the effects were reversed by pre-treatment with Res. In addition, Res activated nuclear factor erythroid 2-related factor 2 (Nrf2) and NAD-dependent protein deacetylase sirtuin-1 (SIRT1), that was reversed by their inhibitors Brusatol and EX527, and subsequently abolished Res-induced upregulation of FPN in the treated cells. Knock-down of FPN partially reduced Res-mediated suppression of macrophage ferroptosis, whereas over-expression of FPN enhanced the effects. Adoptive transfer of FPN over-expressing bone marrow-derived macrophages (BMDMs) reduced lung inflammation and injury, in association with reduced lung neutrophil infiltrates, and expression of TNF-α, IL-6 in the treated mice. CONCLUSION: Res suppressed AECOPD partially through activation of Nrf2/FPN signaling and subsequent suppression of macrophage ferroptosis. FPN would be a potential therapeutic target in the treatment of AECOPD.