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• W3016870576 abstract "Humans, because of the loss of the uricase gene, have higher levels of serum urate (SUA) than most other mammals, prompting speculation of potential advantages of higher SUA levels. Others have proposed the role of urate as a chemical danger signal, and gout research has clearly shown urate crystal deposition stimulates a profound inflammatory response. Recently, we created a hyperuricemia mouse model through the insertion of a point mutation (Q140K) into the critical urate transporter ABCG2. Though these animals are hyperuricemic, they display no evidence of crystal deposition. In addition, we observed reduction in ABCG2 mediated intestinal secretion was key in the animal’s urate homeostatic mechanisms and the cause of the hyperuricemia. Thus, we hypothesized gastrointestinal infection may lead to dramatic changes in serum urate levels. In a mouse model of shigella infection we found 2-fold increases in serum urate in infected mice. Because the intestines are a critical source of cytokines and other immune system signal, we next sought to better understand the role for urate. Is it a byproduct of infection or a signal that helps coordinate an immune response and host defense? To answer this question, we challenged the two mice genotypes, WT and the hyperuricemic Q140K, with intraperitoneally injected 100μg lipopolysaccharide (LPS, E. coli 055: B5). At baseline, pre-LPS, a comparison between WT and the Q140K mice revealed no significant differences in our panel of cytokines. However, twenty-four hours after LPS challenge showed significantly greater increases in the Th2 cytokines: IL-5, -10, and IL-13 (100%, 168%, and 100% respectively) in the hyperuricemic Q140K mice. We observed no differences in IL-4 production, Th1 cytokines IL-2, and TNF, or chemokines Ccl5, and Cxcl10 between the two genotypes. These results suggest the increased Th2 cytokine production in Q140K mice is due to hyperuricemia. In addition to the Th2 cytokines, vascular endothelial growth factor (VEGF) levels were increased by 2.3-fold in Q140K mice as compared to WT in response to LPS challenge, potentially influencing the Th2 cytokine production and moderating immunopathology. We conclude hyperuricemia pre-conditions the immune system, specifically Th2 cytokine, resulting in far greater responses to potential infectious pathogens and ultimately inhibiting disease progression. Support or Funding Information NIH, NIDDK" @default.
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• W3016870576 date "2020-04-01" @default.
• W3016870576 modified "2023-10-14" @default.
• W3016870576 title "Significant role for intestinal urate transporters in host defense" @default.
• W3016870576 doi "https://doi.org/10.1096/fasebj.2020.34.s1.06487" @default.
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