In response to infection, polymorphonuclear neutrophils (PMN) are recruited in the infectious sites, and employ three major strategies to fight against the microbes including phagocytosis, degranulation, and neutrophil extracellular traps (NETs). NETs are a meshwork of chromatin fibers mixed with granule-derived antimicrobial peptides and enzymes, which trap and kill the bacteria extracellularly. In this study, by using a mouse sepsis model, we identified a novel mechanism by which NETs induce macrophage (Mϕ) pyroptosis, a caspase-1-dependent regulated cell death. We show that NET-derived HMGB1, acting through RAGE and dynamin-dependent signaling, triggers an intra-Mϕ cascade of molecular events including cathepsin B (CatB) release from the ruptured lysosomes, followed by pyroptosome formation and caspase-1 activation, and subsequent Mϕ pyroptosis. The study further demonstrates that Mϕ pyroptosis augments inflammatory responses following sepsis. These findings shed light on the proinflammatory role of NETs in mediating PMN–Mϕ interaction, which therefore influences the progress of inflammation following infection.
Hemorrhagic shock (HS) often renders patients more susceptible to lung injury by priming for an exaggerated response to a second infectious stimulus. Acute lung injury (ALI) is a major component of multiple organ dysfunction syndrome following HS and regularly serves as a major cause of patient mortality. The lung vascular endothelium is an active organ that has a central role in the development of ALI through synthesizing and releasing of a number of inflammatory mediators. Cell pyroptosis is a caspase-1-dependent regulated cell death, which features rapid plasma membrane rupture and release of proinflammatory intracellular contents. In this study, we demonstrated an important role of HS in priming for LPS-induced lung endothelial cell (EC) pyroptosis. We showed that LPS through TLR4 activates Nlrp3 (NACHT, LRR, and PYD domains containing protein 3) inflammasome in mouse lung vascular EC, and subsequently induces caspase-1 activation. However, HS induced release of high-mobility group box 1 (HMGB1), which acting through the receptor for advanced glycation end products initiates EC endocytosis of HMGB1, and subsequently triggers a cascade of molecular events, including cathepsin B release from ruptured lysosomes followed by pyroptosome formation and caspase-1 activation. These HS-induced events enhance LPS-induced EC pyroptosis. We further showed that lung vascular EC pyroptosis significantly exaggerates lung inflammation and injury. The present study explores a novel mechanism underlying HS-primed ALI and thus presents a potential therapeutic target for post-HS ALI.
A reduction in endogenously generated reactive oxygen species in vivo delays benzo(α)pyrene (BaP)-accelerated atherosclerosis, as revealed in hypercholesterolemic mice overexpressing Cu/Znsuperoxide dismutase (SOD) and/or catalase. To understand the molecular events involved in this protective action, we studied the effects of Cu/Zn-SOD and/or catalase overexpression on BaP detoxification and on aryl hydrocarbon receptor (AhR) expression and its target gene expression in mouse aortic endothelial cells (MAECs). Our data demonstrate that overexpression of Cu/Zn-SOD and/or catalase leads to an 18-to 20-fold increase in the expression of AhR protein in MAECs. After BaP exposure, the amount of AhR binding to the cytochrome P450 (CYP) 1A1 promoter was significantly greater, and the concentrations of BaP reactive intermediates were significantly less in MAECs overexpressing Cu/Zn-SOD and/or catalase than in wild-type cells. In addition, the BaPinduced CYP1A1 and 1B1 protein levels and BaP-elevated glutathione S-transferase (GST) activity were significantly higher in these transgenic cells, in parallel with elevated GSTp1, CYP1A1, and CYP1B1 mRNA levels, compared to wild-type MAECs. Moreover, knockdown of AhR with RNA interference diminished the Cu/Zn-SOD and catalase enhancement of CYP1A1 expression, GST activity, and BaP detoxification. These data demonstrate that overexpression of Cu/Zn-SOD and/or catalase is associated with upregulation of AhR and its target genes, such as xenobiotic-metabolizing enzymes. KeywordsBenzo(α)pyrene; Aryl hydrocarbon receptor; Endothelial cells; Cu/Zn-superoxide dismutase; Catalase; Free radicals Polycyclic aromatic hydrocarbons (PAHs) are a class of chemical carcinogens found in cigarette smoke, automobile exhaust, and foods cooked at high temperature (reviewed in Refs. [17,33]). Benzo(α) pyrene (BaP), a representative PAH compound, has been shown to target vascular cells and accelerate the development of atherosclerosis [4]. A recent study from our laboratory demonstrated that over-expression of Cu/Zn-superoxide dismutase (SOD) and/or catalase inhibited BaP-accelerated atherosclerosis in hypercholesterolemic mice [42].*Corresponding author. Fax: +1 615 321 2949. Hyang@mmc.edu (H. Yang), Zguo@mmc.edu (Z. Guo). NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptHowever, the mechanism underlying the inhibitory action of these antioxidant enzymes on BaP-induced atherosclerosis has not been defined.It is generally accepted that the pathologic action of BaP results primarily from its reactive intermediates, which could be generated by multiple simultaneous or sequential metabolic transformations [13]. Initially, BaP is metabolized by cytochrome P450 (CYP) enzymes to epoxides, which can be hydrated to various dihydrodiols by epoxide hydrolase. 8-dihydro-BaP can be further oxidized to by CYPs [9]. BPDE is capable of binding covalently to DNA to form BPDE-DNA adducts, which is a crucial step leading to DNA mutations [10]. BaP-induced bulky DNA a...
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