title: Xanthine Oxidase Induces Foam Cell Formation through LOX-1 and NLRP3 Activation.
abstract: OBJECTIVE
  Xanthine oxidase catalyzes the oxidation of xanthine to uric acid. This process generates excessive reactive oxygen species (ROS) that play an important role in atherogenesis. Recent studies show that LRR and PYD domains-containing protein 3 (NLRP3), a component of the inflammasome, may be involved in the formation of foam cells, a hallmark of atherosclerosis. This study was designed to study the role of various scavenger receptors and NLRP3 inflammasome in xanthine oxidase and uric acid-induced foam cell formation.
  
  
  RESULTS
  Human vascular smooth muscle cells (VSMCs) and THP-1 macrophages were treated with xanthine oxidase or uric acid. Xanthine oxidase treatment (of both VSMCs and THP-1 cells) resulted in foam cell formation in concert with generation of ROS and expression of cluster of differentiation 36 (CD36) and oxidized low density lipoprotein (lectin-like) receptor 1 (LOX-1), but not of scavenger receptor A (SRA). Uric acid treatment resulted in foam cell formation, ROS generation and expression of CD36, but not of LOX-1 or SRA. Further, treatment of cells with xanthine oxidase, but not uric acid, activated NLRP3 and its downstream pro-inflammatory signals- caspase-1, interleukin (IL)-1β and IL-18. Blockade of LOX-1 or NLRP3 inflammasome with specific siRNAs reduced xanthine oxidase-induced foam cell formation, ROS generation and activation of NLRP3 and downstream signals.
  
  
  CONCLUSIONS
  Xanthine oxidase induces foam cell formation in large part through activation of LOX-1 - NLRP3 pathway in both VSMCs and THP-1 cells, but uric acid-induced foam cell formation is exclusively through CD36 pathway. Further, LOX-1 activation is upstream of NLRP3 activation. Graphical Abstract Steps in the formation of foam cells in response to xanthine oxidase and uric acid. Xanthine oxidase stimulates LOX-1 expression on the cell membrane of macrophages and vascular smooth muscle cells (VSMCs) and increases generation of ROS, which activate NLRP3 inflammasome and downstream pro-inflammatory mediators such as Caspase-1, IL-1β and IL-18. Xanthine oxidase also induces CD36 expression. Activation of both LOX-1 and CD36 (LOX-1> > CD36) participates in the transformation of macrophages and VSMCs into foam cells. Uric acid formed from xanthine-xanthine oxidase interaction stimulates CD36 expression and triggers foam cell formation independent of NLRP3 activation.
authors.affiliation: Department of Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. daiyaoh@163.com.|Department of Internal Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China, 230022. daiyaoh@163.com.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China, 230022.
authors.forename: Yongxiang
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Internal Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, People's Republic of China, 230022.
authors.forename: Zhigao
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA.
authors.forename: Srikanth
authors.initials: S
authors.lastname: Vallurupalli
authors.affiliation: Department of Medicine, Central Arkansas Veterans Healthcare System, University of Arkansas for Medical Sciences, Little Rock, AR, 72205, USA. MehtaJL@UAMS.edu.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
mesh_terms: D018955:CD36 Antigens / Q000378:metabolism; D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation / Q000187:drug effects*; D005487:Foam Cells / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects* / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000201:enzymology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D051117:Scavenger Receptors, Class A / Q000378:metabolism; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014162:Transfection; D014527:Uric Acid / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000494:pharmacology*
chemical_list: D018955:CD36 Antigens; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C495137:OLR1 protein, human; D017382:Reactive Oxygen Species; D051117:Scavenger Receptors, Class A; D051127:Scavenger Receptors, Class E; D014527:Uric Acid; D014969:Xanthine Oxidase
keywords: CD36; Foam cell; Lox-1; Scavenger receptors; Uric acid; Xanthine oxidase