Monosodium urate crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response
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
Isidoro Cobo
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Anyan Cheng
Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
Jessica Murillo-Saich
Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
Roxana Coras
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
Alyssa Torres
Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA
Yohei Abe
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Addison J. Lana
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Johannes Schlachetzki
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Ru Liu-Bryan
Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA; VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
Robert Terkeltaub
Division of Rheumatology, Allergy and Immunology. UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093, USA; VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA 92161, USA
Elsa Sanchez-Lopez
Department of Orthopedic Surgery, University of California San Diego, La Jolla, San Diego, CA 92093, USA
Christopher K. Glass
Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, San Diego, CA 92093, USA; Corresponding author
Monica Guma
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; Corresponding author
Summary: 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.
