Hyperuricemia remodels the serum proteome toward a higher inflammatory state

Cabău, Georgiana; Gaal, Orsolya; Badii, Medeea; Nica, Valentin; Mirea, Andreea-Manuela; Hotea, Ioana; Pamfil, Cristina; Popp, Radu A.; Netea, Mihai G.; Rednic, Simona; Crișan, Tania O.; Joosten, Leo A.B.

doi:10.1016/j.isci.2023.107909

Cited by 5 publications

(11 citation statements)

References 92 publications

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“…The methodology employed dual recognition by oligonucleotide-labelled antibody probe pairs and DNAcoupled quantitative PCR, designed to detect speci c immunoregulatory proteins below mass spectrometry detection limits 44 . Upregulated serum immunoregulatory proteins in AH group included the mTOR effector 4E-BP1, IL-18R1, multiple growth factors, chemokines, and members of the IL-6 cytokine and TNF superfamily 44 . A Th17 cell signature, and increases in in ammation-dampening IL-10 and FGF21 also were identi ed 44 .…”

Section: Discussionmentioning

confidence: 99%

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

Sanchez,

Campeau,

Liu-Bryan

et al. 2024

Preprint

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Background Urate-lowering treatment (ULT) to target with xanthine oxidase inhibitors (XOIs) paradoxically causes early increase in gouty arthritis flares. Because delayed reduction in flare burden is mechanistically unclear, we tested for ULT inflammation responsiveness markers. Methods Unbiased proteomics analyzed blood samples (baseline, 48 weeks ULT) in two, independent ULT out trial cohorts (n = 19, n = 30). STRING-db and multivariate analyses supplemented determinations of altered proteins via Wilcoxon matched pairs signed rank testing in XOI ULT responders. Mechanistic studies characterized proteomes of cultured XOI-treated murine bone marrow macrophages (BMDMs). Results At 48 weeks ULT, serum urate normalized in all gout patients, and flares declined, with significantly altered proteins (p < 0.05) in clustering and proteome networks in sera and peripheral blood mononuclear cells. Serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains and chemokine PPBP/CXCL7, and increased urate crystal phagocytosis inhibitor sCD44. In both cohorts, a treatment-emergent serum interactome included key gouty inflammation mediators (C5, IL-1B, CXCL8, IL6). Last, febuxostat inhibited complement activation pathway proteins in cultured BMDMs. Conclusions Reduced gout flares are kinked with a XOI-treatment emergent complement- and inflammation-regulatory serum protein interactome. Serum and leukocyte proteomes could help identify onset of anti-inflammatory responsiveness to ULT in gout. Trial Registration ClinicalTrials.gov Identifier: NCT02579096, posted October 19, 2015

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Section: Discussionmentioning

confidence: 99%

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

Sanchez,

Campeau,

Liu-Bryan

et al. 2024

Preprint

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show abstract

Section: Discussionmentioning

confidence: 99%

“…A pro-inflammatory serum proteome signature was recently characterized in asymptomatic hyperuricemia (AH) by targeted proteomics ( 46 ). The approach used the Olink Target 96 Inflammation Panel ™ ( 46 ), distinct from the unbiased mass spectrometry-based approach utilized in the current study. The methodology employed dual recognition by oligonucleotide-labelled antibody probe pairs and DNA-coupled quantitative PCR, designed to detect specific immunoregulatory proteins below mass spectrometry detection limits ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

“…The approach used the Olink Target 96 Inflammation Panel ™ ( 46 ), distinct from the unbiased mass spectrometry-based approach utilized in the current study. The methodology employed dual recognition by oligonucleotide-labelled antibody probe pairs and DNA-coupled quantitative PCR, designed to detect specific immunoregulatory proteins below mass spectrometry detection limits ( 46 ). Upregulated serum immunoregulatory proteins in AH group included the mTOR effector 4E-BP1, IL-18R1, multiple growth factors, chemokines, members of the IL-6 cytokine and TNF superfamily, with a Th17 cell signature, and increases in inflammation-dampening IL-10 and FGF21 also identified ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

“…The methodology employed dual recognition by oligonucleotide-labelled antibody probe pairs and DNA-coupled quantitative PCR, designed to detect specific immunoregulatory proteins below mass spectrometry detection limits ( 46 ). Upregulated serum immunoregulatory proteins in AH group included the mTOR effector 4E-BP1, IL-18R1, multiple growth factors, chemokines, members of the IL-6 cytokine and TNF superfamily, with a Th17 cell signature, and increases in inflammation-dampening IL-10 and FGF21 also identified ( 46 ). Using the same targeted serum proteomics approach, a small sub-study of 13 subjects before and 3 months into successful XOI-based treat to target ULT also revealed significant downregulation of LIF-R. CDCP1, IL-18, NT-3, IL10RB, CCL28, CCL11, and SLAMF1 ( 46 ).…”

Section: Discussionmentioning

confidence: 99%

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Sustained xanthine oxidase inhibitor treat to target urate lowering therapy rewires a tight inflammation serum protein interactome

Sanchez,

Campeau,

Liu-Bryan

et al. 2024

Preprint

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Background: Effective xanthine oxidoreductase inhibition (XOI) urate-lowering treatment (ULT) to target significantly reduces gout flare burden and synovitis between 1-2 years therapy, without clearing all monosodium urate crystal deposits. Paradoxically, treat to target ULT is associated with increased flare activity for at least 1 year in duration on average, before gout flare burden decreases. Since XOI has anti-inflammatory effects, we tested for biomarkers of sustained, effective ULT that alters gouty inflammation. Methods: We characterized the proteome of febuxostat-treated murine bone marrow macrophages. Blood samples (baseline and 48 weeks ULT) were analyzed by unbiased proteomics in febuxostat and allopurinol ULT responders from two, independent, racially and ethnically distinct comparative effectiveness trial cohorts (n=19, n=30). STRING-db and multivariate analyses supplemented determinations of significantly altered proteins via Wilcoxon matched pairs signed rank testing. Results: The proteome of cultured IL-1b-stimulated macrophages revealed febuxostat-induced anti-inflammatory changes, including for classical and alternative pathway complement activation pathways. At 48 weeks ULT, with altered purine metabolism confirmed by serum metabolomics, serum urate dropped >30%, to normal (<6.8 mg/dL) in all the studied patients. Overall, flares declined from baseline. Treated gout patient sera and peripheral blood mononuclear cells (PBMCs) showed significantly altered proteins (p<0.05) in clustering and proteome networks. CRP was not a useful therapy response biomarker. By comparison, significant serum proteome changes included decreased complement C8 heterotrimer C8A and C8G chains essential for C5b-9 membrane attack complex assembly and function; increase in the NLRP3 inflammasome activation promoter vimentin; increased urate crystal phagocytosis inhibitor sCD44; increased gouty inflammation pro-resolving mediator TGFB1; decreased phagocyte-recruiting chemokine PPBP/CXCL7, and increased monocyte/macrophage-expressed keratin-related proteins (KRT9,14,16) further validated by PBMC proteomics. STRING-db analyses of significantly altered serum proteins from both cohorts revealed a tight interactome network including central mediators of gouty inflammation (eg, IL-1B, CXCL8, IL6, C5). Conclusions: Rewiring of inflammation mediators in a tight serum protein interactome was a biomarker of sustained XOI-based ULT that effectively reduced serum urate and gout flares. Monitoring of the serum and PBMC proteome, including for changes in the complement pathway could help determine onset and targets of anti-inflammatory changes in response to effective, sustained XOI-based ULT. Trial Registration: ClinicalTrials.gov Identifier: NCT02579096

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Soluble urate-induced effects on cytokine production in vitro – Assessment of methodologies and cell types

Liu,

Klück,

Kischkel

et al. 2024

Cytokine

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Hyperuricemia remodels the serum proteome toward a higher inflammatory state

Cited by 5 publications

References 92 publications

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

Effective xanthine oxidase inhibitor urate lowering therapy in gout is linked to an emergent serum protein interactome of complement activation and inflammation modulators

Sustained xanthine oxidase inhibitor treat to target urate lowering therapy rewires a tight inflammation serum protein interactome

Soluble urate-induced effects on cytokine production in vitro – Assessment of methodologies and cell types

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