Serum amyloid A (SAA) is a high-density apolipoprotein whose plasma levels can increase more than 1000-fold during a severe acute-phase inflammatory response and are more modestly elevated in chronic inflammation. SAA is thought to play important roles in innate immunity, but its biological activities have not been completely delineated. We previously reported that SAA deficiency protects mice from developing abdominal aortic aneurysms (AAAs) induced by chronic angiotensin II (AngII) infusion. Here, we report that SAA is required for AngII-induced increases in interleukin-1β (IL-1β), a potent proinflammatory cytokine that is tightly controlled by the Nod-like receptor protein 3 (NLRP3) inflammasome and caspase-1 and has been implicated in both human and mouse AAAs. We determined that purified SAA stimulates IL-1β secretion in murine J774 and bone marrow–derived macrophages through a mechanism that depends on NLRP3 expression and caspase-1 activity, but is independent of P2X7 nucleotide receptor (P2X7R) activation. Inhibiting reactive oxygen species (ROS) by N-acetyl-l-cysteine or mito-TEMPO and inhibiting activation of cathepsin B by CA-074 blocked SAA–mediated inflammasome activation and IL-1β secretion. Moreover, inhibiting cellular potassium efflux with glyburide or increasing extracellular potassium also significantly reduced SAA–mediated IL-1β secretion. Of note, incorporating SAA into high-density lipoprotein (HDL) prior to its use in cell treatments completely abolished its ability to stimulate ROS generation and inflammasome activation. These results provide detailed insights into SAA–mediated IL-1β production and highlight HDL's role in regulating SAA's proinflammatory effects.
Digital Object Identifier (DOI)
This work was supported by National Institutes of Health Grant HL134731 (to N. R. W) and Institutional Development Award (IDeA), National Institute of Health NIGMS Grant P20 GM103527.
This article contains Fig. S1.
Shridas, Preetha; de Beer, Maria C.; and Webb, Nancy R., "High-Density Lipoprotein Inhibits Serum Amyloid A-Mediated Reactive Oxygen Species Generation and NLRP3 Inflammasome Activation" (2018). Internal Medicine Faculty Publications. 158.
Available for download on Friday, July 05, 2019