Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response.

Cell Rep

Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193 Bellaterra, Barcelona, Spain; VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. Electronic address:

Published: March 2022

Monosodium urate crystals (MSUc) induce inflammation in vivo without prior priming, raising the possibility of an initial cell-autonomous phase. Here, using genome-wide transcriptomic analysis and biochemical assays, we demonstrate that MSUc alone induce a metabolic-inflammatory transcriptional program in non-primed human and murine macrophages that is markedly distinct to that induced by LPS. Genes uniquely upregulated in response to MSUc belong to lipid and amino acid metabolism, glycolysis, and SLC transporters. This upregulation leads to a metabolic rewiring in sera from individuals and mice with acute gouty arthritis. Mechanistically, the initiating inflammatory-metabolic changes in acute gout flares are regulated through a persistent expression and increased binding of JUN to the promoter of target genes through JNK signaling-but not P38-in a process that is different than after LPS stimulation and independent of inflammasome activation. Finally, pharmacological JNK inhibition limits MSUc-induced inflammation in animal models of acute gouty inflammation.

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989403PMC
http://dx.doi.org/10.1016/j.celrep.2022.110489DOI Listing

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