Monosodium Urate Crystals Regulate a Unique JNK-dependent Macrophage Metabolic and Inflammatory Response

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2022 Mar 9

PMID 35263587

Authors

Isidoro Cobo

Anyan Cheng

Jessica Murillo-Saich

Roxana Coras

Alyssa Torres

Yohei Abe

Addison J Lana

Johannes Schlachetzki

Ru Liu-Bryan

Robert Terkeltaub

Elsa Sanchez-Lopez

Christopher K Glass

Monica Guma

Affiliations

Soon will be listed here.

Abstract

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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