High-mobility group box 1 suppresses resolvin D1-induced phagocytosis via induction of resolvin D1-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase

Abstract

High-mobility group box 1 (HMGB1) enhances inflammatory reactions by potentiating the activity of pro-inflammatory mediators and suppressing the phagocytosis of apoptotic neutrophils. However, the effects of HMGB1 on phagocytosis induced by pro-resolving mediators, such as resolvins, have not been studied up until this point. In this study, we investigated the effects and underlying mechanism of HMGB1 on resolvin D1-induced phagocytosis of MDA-MB-231 cells, which were selected as a model system based on their phagocytic capability and ease of transfecting them with a plasmid or siRNA in several cancer cell lines. Then we confirmed effects of HMGB1 in THP-1 cells. Resolvin D1 (RvD1) enhanced phagocytosis in MDA-MB-231 and THP-1 cells. HMGB1 suppressed RvD1-induced phagocytosis in MDA-MB.231 and THP-1 cells. HMGB1 dose-dependently induced the expression of 15-hydroxyprostaglandin dehydrogenase (15-PGDH), the inactivating enzyme in pro-resolving lipid mediators such as RvE1 and RvD1. Involvement of 15-PGDH in-HMGB-1-induced suppression of phagocytosis was examined using siRNA of 15-PGDH or 15-PGDH inhibitor, TD23. Surprisingly, the silencing of 15-PGDH increased phagocytotic activity of MDA-MB-231 cells. TD23 also enhanced phagocytosis of MDA-MB-231 and THP-1 cells. In conclusion, the release of HMGB1 during the inflammatory phase induces 15-PGDH expression, which suppresses the phagocytotic activity of macrophages. These processes might be involved in the mechanism that blocks the resolution of inflammation, thereby allowing acute inflammation to progress to chronic inflammation.

Carcinogenesis: Failure of resolution of inflammation?

“…Alarmins such as high-mobility group box 1 (HMGB1) can disrupt the resolution of inflammation by inhibiting macrophage efferocytosis induced by SPMs ( Kang et al, 2015 ). HMGB1 plays an important role in maintaining inflammation and can be actively released from various immune cells such as macrophages, monocytes, NK cells, dendritic cells, and endothelial cells, as well as from dead (e.g necrotic) cells ( Scaffidi, Misteli, & Bianchi, 2002 ).…”

“…HMGB1 enhances inflammatory reactions by potentiating the activity of pro-inflammatory mediators such as LPS and cytokines, and by suppressing the phagocytosis of apoptotic neutrophils ( Banerjee et al, 2011 ; Liu et al, 2008 ). HMGB1 suppresses resolvin D1-induced phagocytosis via induction of resolvin D1-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase ( Kang et al, 2015 ). HMGB1 suppressed RvD1-enhanced phagocytosis of MDA-MB-231 cancer cells and gene silencing of HMGB1 restored the phagocytic capability of MDA-MB-231 cells ( Kang et al, 2015 ).…”

“…HMGB1 suppresses resolvin D1-induced phagocytosis via induction of resolvin D1-inactivating enzyme, 15-hydroxyprostaglandin dehydrogenase ( Kang et al, 2015 ). HMGB1 suppressed RvD1-enhanced phagocytosis of MDA-MB-231 cancer cells and gene silencing of HMGB1 restored the phagocytic capability of MDA-MB-231 cells ( Kang et al, 2015 ). Hepatocellular carcinoma ensues in the presence of excessive hepatic apoptosis and necroptosis in the tumor microenvironment which directs lineage commitment to either hepatocellular carcinoma or intrahepatic cholangiocarcinoma ( Seehawer et al, 2018 ).…”

Aryl Hydrocarbon Receptor Role in Co-Ordinating SARS-CoV-2 Entry and Symptomatology: Linking Cytotoxicity Changes in COVID-19 and Cancers; Modulation by Racial Discrimination Stress

“…Such data indicate a role for pre-existent high-risk medical conditions–induced variations in SPMs in the suboptimal initial ‘cytokine storm’ and later anti-viral response evident in these patients. Pre-existent, cytokine-, or stress-induced increase in gut dysbiosis/permeability may be relevant to this, given that gut permeability-induced HMGB1 suppresses the RvD1 resolution of activated neutrophils [ 76 ]. Chronic heart failure patients show a decrease response to RvD1 and RvD2 in activated CD8+ T cells, mediated by a decrease in the GPR32 receptor [ 77 ].…”

“…Butyrate also inhibits cells involved in the ‘cytokine storm’, including macrophages and neutrophils [ 104 ], with its inhibition of COX2-driven attachment of monocytes to endothelial cells [ 105 ], indicating an impact of butyrate on embolism formation and atherosclerosis [ 106 ]. In the lung, butyrate suppresses HMGB1 induction to infection, suggesting that it will act to prevent the HMGB1 inhibition of RvD1 and the RvD1 resolution of activated neutrophils [ 76 ]. It has been recently proposed that the effects of gut dysbiosis are crucially mediated by its regulation of systemic mitochondrial function, especially in immune cells [ 44 ].…”