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

• DOI: 10.1016/j.celrep.2022.110489
• Publication Date: 2022-03-08T21:16:20Z
• Authors: Isidoro Cobo; Anyan Cheng; Jessica Murillo-S...; Roxana Coras; Alyssa Torres; Yohei Abe; Addison J. Lana; Johannes Schlache...; Ru Liu-Bryan; Robert Terkeltaub; Elsa Sanchez-Lopez; Christopher K. Glass; Monica Guma
• Keywords: Lipopolysaccharides; 0301 basic medicine; 570; Gouty; QH301-705.5; SLC2A1; Medical Physiology; 610; macrophage; Mice; 03 medical and health sciences; gout; Genetics; 2.1 Biological and endogenous factors; Animals; transcriptional regulation; Biology (General); MSU crystals; Inflammation; AP-1 activation; Arthritis, Gouty; Arthritis; Inflammatory and immune system; Macrophages; Biological Sciences; glycolysis; Uric Acid; Biological sciences; Biochemistry and Cell Biology; JNK

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.