Urate-induced epigenetic modifications in myeloid cells

M. Badii, O. I. Gaal, M. C. Cleophas, V. Klück, R. Davar, E. Habibi, S. T. Keating, B. Novakovic, M. M. Helsen, N. Dalbeth, L. K. Stamp, D. Macartney-Coxson, A. J. Phipps-Green, H. G. Stunnenberg, C. A. Dinarello, T. R. Merriman, M. G. Netea, T. O. Crişan, L. A.B. Joosten

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

6 Citaten (Scopus)

Samenvatting

Objectives: Hyperuricemia is a metabolic condition central to gout pathogenesis. Urate exposure primes human monocytes towards a higher capacity to produce and release IL-1β. In this study, we assessed the epigenetic processes associated to urate-mediated hyper-responsiveness. Methods: Freshly isolated human peripheral blood mononuclear cells or enriched monocytes were pre-treated with solubilized urate and stimulated with LPS with or without monosodium urate (MSU) crystals. Cytokine production was determined by ELISA. Histone epigenetic marks were assessed by sequencing immunoprecipitated chromatin. Mice were injected intraarticularly with MSU crystals and palmitate after inhibition of uricase and urate administration in the presence or absence of methylthioadenosine. DNA methylation was assessed by methylation array in whole blood of 76 participants with normouricemia or hyperuricemia. Results: High concentrations of urate enhanced the inflammatory response in vitro in human cells and in vivo in mice, and broad-spectrum methylation inhibitors reversed this effect. Assessment of histone 3 lysine 4 trimethylation (H3K4me3) and histone 3 lysine 27 acetylation (H3K27ac) revealed differences in urate-primed monocytes compared to controls. Differentially methylated regions (e.g. HLA-G, IFITM3, PRKAB2) were found in people with hyperuricemia compared to normouricemia in genes relevant for inflammatory cytokine signaling. Conclusion: Urate alters the epigenetic landscape in selected human monocytes or whole blood of people with hyperuricemia compared to normouricemia. Both histone modifications and DNA methylation show differences depending on urate exposure. Subject to replication and validation, epigenetic changes in myeloid cells may be a therapeutic target in gout.

Originele taal-2Engels
Artikelnummer202
TijdschriftArthritis Research and Therapy
Volume23
Nummer van het tijdschrift1
DOI's
StatusGepubliceerd - dec. 2021
Extern gepubliceerdJa

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