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

被引：39

作者：

Cobo, Isidoro ^{[1
]}

Cheng, Anyan ^{[2
]}

Murillo-Saich, Jessica ^{[2
]}

Coras, Roxana ^{[2
,3
]}

Torres, Alyssa ^{[2
]}

Abe, Yohei ^{[1
]}

Lana, Addison J. ^{[1
]}

Schlachetzki, Johannes ^{[1
]}

Liu-Bryan, Ru ^{[2
,4
]}

Terkeltaub, Robert ^{[2
,4
]}

Sanchez-Lopez, Elsa ^{[5
]}

Glass, Christopher K. ^{[1
]}

Guma, Monica ^{[2
,3
,4
]}

机构：

[1] Univ Calif San Diego, Dept Cellular & Mol Med, San Diego, CA 92093 USA

[2] UCSD Sch Med, Div Rheumatol Allergy & Immunol, 9500 Gilman Dr, La Jolla, CA 92093 USA

[3] Autonomous Univ Barcelona, Dept Med, Pl Civ, Barcelona 08193, Spain

[4] VA San Diego Healthcare Syst, 3350 La Jolla Village Dr, San Diego, CA 92161 USA

[5] Univ Calif San Diego, Dept Orthoped Surg, San Diego, CA 92093 USA

来源：

CELL REPORTS | 2022年 / 38卷 / 10期

关键词：

TRANSCRIPTION FACTORS; OXIDATIVE STRESS; CELL; AP-1; JUN; MONOHYDRATE; ACTIVATION; INTERLEUKIN-1-BETA; EXPRESSION; PATHWAY;

D O I：

10.1016/j.celrep.2022.110489

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：22

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