Urate-induced epigenetic modifications in myeloid cells

Arthritis Research & Therapy

A. J. Phipps-Green¹  T. R. Merriman²  M. C. Cleophas³  V. Klück³  S. T. Keating³  C. A. Dinarello⁴  M. G. Netea⁵  T. O. Crişan⁶  O. I. Gaal⁶  M. Badii⁶  L. A. B. Joosten⁶  N. Dalbeth⁷  L. K. Stamp⁸  E. Habibi⁹  B. Novakovic⁹  H. G. Stunnenberg⁹  R. Davar⁹  M. M. Helsen^1,10  D. Macartney-Coxson^1,11 

[1] Department of Biochemistry, University of Otago, Dunedin, New Zealand;Department of Biochemistry, University of Otago, Dunedin, New Zealand;Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, USA;Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 8, 6525 GA, Nijmegen, The Netherlands;Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 8, 6525 GA, Nijmegen, The Netherlands;Department of Medicine, University of Colorado Denver, 80045, Aurora, CO, USA;Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 8, 6525 GA, Nijmegen, The Netherlands;Human Genomics Laboratory, University of Medicine and Pharmacy of Craiova, Craiova, Romania;Department of Medical Genetics, Iuliu Hațieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania;Department of Internal Medicine and Radboud Institute for Molecular Life Sciences (RIMLS), Radboud University Medical Center, Geert Grooteplein 8, 6525 GA, Nijmegen, The Netherlands;Department of Medicine, University of Auckland, Auckland, New Zealand;Department of Medicine, University of Otago Christchurch, Christchurch, New Zealand;Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, The Netherlands;Department of Rheumatology, Radboud University Medical Center, Nijmegen, The Netherlands;Human Genomics, Institute of Environmental Science and Research (ESR), Wellington, New Zealand;

关键词: Hyperuricemia;    Cytokines;    Epigenetics;    DNA methylation;    Gout;   

DOI  :  10.1186/s13075-021-02580-1

来源: Springer

【 摘 要 】

ObjectivesHyperuricemia 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.MethodsFreshly 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.ResultsHigh 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.ConclusionUrate 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.

【 授权许可】

CC BY