Xanthine Oxidoreductase Promotes the Inflammatory State of Mononuclear Phagocytes through Effects on Chemokine Expression, Peroxisome Proliferator-activated Receptor-γ Sumoylation, and HIF-1α

Abstract

The protective effects of pharmacological inhibitors of xanthine oxidoreductase (XOR) have implicated XOR in many inflammatory diseases. Nonetheless, the role played by XOR during inflammation is poorly understood. We previously observed that inhibition of XOR within the inflammatory mononuclear phagocytes (MNP) prevented neutrophil recruitment during adoptive transfer demonstrating the role of XOR in MNP-mediated neutrophil recruitment. To further explore the role of XOR in the inflammatory state of MNP, we studied MNP isolated from inflammatory lungs combined with analyses of MNP cell lines. We demonstrated that XOR activity was increased in inflammatory MNP following insufflation of Th-1 cytokines in vivo and that activity was specifically increased by MNP differentiation. Inhibition of XOR reduced levels of CINC-1 secreted by MNP. Expression of peroxisome proliferatoractivated receptor ␥ (PPAR␥) in purified rat lung MNP and MNP cell lines reflected both the presence of PPAR␥ isoforms and PPAR␥ SUMOylation, and XOR inhibitors increased levels of SUMO-PPAR␥ in MNP cell lines. Both ectopic overexpression of XOR cDNA and uric acid supplementation reduced SUMO-PPAR␥ in MNP cells. Levels of the M2 markers CD36, CD206, and arginase-1 were modulated by uric acid and oxonic acid, whereas siRNA to SUMO-1 or PIAS-1 also reduced arginase-1 in RAW264.7 cells. We also observed that HIF-1␣ was increased by XOR inhibitors in inflammatory MNP and in MNP cell lines. These data demonstrate that XOR promotes the inflammatory state of MNP through effects on chemokine expression, PPAR␥ SUMOylation, and HIF-1␣ and suggest that strategies for inhibiting XOR may be valuable in modulating lung inflammatory disorders.

Role of Uric Acid Metabolism-Related Inflammation in the Pathogenesis of Metabolic Syndrome Components Such as Atherosclerosis and Nonalcoholic Steatohepatitis

“…XO increased Egr-1 mRNA and protein, as well as the phosphorylation of ERK1/2, while pretreatment with an ERK1/2 inhibitor prevented induction of Egr-1 by XO [78]. In addition, XO reportedly reduced SUMOylation of PPAR γ in inflammatory cells [79]. ROS from XO augment TRB3 expression in podocytes [80].…”

Are either or both hyperuricemia and xanthine oxidase directly toxic to the vasculature? A critical appraisal

“…54 Moreover, oxonate potentially modulates renal transport of UA, and thereby could affect intracellular handling and effects of UA in renal proximal tubular cells. 55 Hence, some mechanisms of renal disease in the in vivo model of oxonic acid-induced hyperuricemia remain to be resolved; ideally, an alternative model of hyperuricemia would help in this task.…”

Linking uric acid metabolism to diabetic complications

“…Several interventional studies have proven the efficacy of hyperuricemia treatments. A randomized controlled study showed that allopurinol prolongs exercise capacity trophil chemoattractant secretion from mononuclear phagocytes is reduced, and small ubiquitin-like modifier of PPARγ and hypoxia-inducible factor 1α levels are increased [92] . Febuxostat activates mitogen-activated protein kinase phosphatase-1 and inhibits inflammation by lipopolysaccharide stimulation through the inhibition of ROS generation [93] .…”