Monosodium Urate Crystals regulate a unique JNK-dependent macrophage metabolic and inflammatory response

Abstract

How macrophages are programmed to respond to monosodium urate crystals (MSUc) is incompletely understood partly due to the use of a toll-like receptor-induced priming step. Here, using genome wide transcriptomic analysis and biochemical assays we demonstrate that MSUc alone induces an in vitro metabolic and inflammatory transcriptional program in both human and murine macrophages markedly distinct from that induced by LPS. Genes uniquely up-regulated in response to MSUc belonged to lipids, glycolysis, and transport of small molecules via SLC transporters pathways. Sera from individuals and mice with acute gouty arthritis provided further evidence for this metabolic rewiring. This distinct macrophage activation may explain the initiating mechanisms in acute gout flares and is regulated through JUN binding to the promoter of target genes through activation of JNK (but not by P38) in a process that is independent of inflammasome activation. Finally, pharmacological JNK inhibition limited MSUc-induced inflammation in animal models of acute gouty inflammation.

A genome-wide association analysis of 2,622,830 individuals reveals new pathogenic pathways in gout

“…Amongst the top enriched DNA-binding proteins were the histone acetylation writers and readers EP300 and BRD4. BRD4 has previously been implicated in the regulation of the NLRP3 inflammasome through regulation of NFκΒ signalling, 41 BRD4 inhibition ameliorates urate crystal-induced gouty arthritis by regulation of pyroptosis in a rat model 42,43 .…”

“…The genes encoding interleukin-1 receptor 1 ( IL1R1 ) and interleukin-6 receptor ( IL6R ) were ranked 15 th and 47 th , respectively. They both are co-localized eQTL in monocytes, are differentially expressed in monocytes exposed to lipopolysaccharide or monosodium urate crystals 43 , their TSSs are contacted by an enhancer, and they have the closest TSS to the lead gout-associated genetic variant. IL-1R1 is antagonized by anakinra, which is an effective option for treatment of gout flares 77 .…”

“…BRD4 has previously been implicated in the regulation of the NLRP3 inflammasome through regulation of NFκΒ signalling, 41 BRD4 inhibition ameliorates urate crystal-induced gouty arthritis by regulation of pyroptosis in a rat model 42 . 43 The kidney is a key organ in urate homeostasis. Given that variation in DNA methylation in the kidney mediates 46% of heritability in kidney function traits 44 , we also identified 328 genetic variants that were kidney meQTL for 576 CpG sites in strong LD (r 2 ≥ 0.8) with a gout genetic association using the Liu et al 44 dataset (Table S18).…”

Single-cell sequencing of PBMC characterizes the altered transcriptomic landscape of classical monocytes in BNT162b2-induced myocarditis

“…Moreover, the metabolic enzymes involved in monocyte-tomacrophage differentiation are known to be closely related to several signaling pathways. For instance, human monocytederived macrophages are reported to upregulate metabolicinflammatory transcriptional programs, including lipid metabolism and glycolytic pathways, upon activation by monosodium urate crystals, which induce inflammation without prior priming (58). The activation of these metabolic gene programs is attributed to the increased binding of JUN to the target promoters (58).…”

“…For instance, human monocytederived macrophages are reported to upregulate metabolicinflammatory transcriptional programs, including lipid metabolism and glycolytic pathways, upon activation by monosodium urate crystals, which induce inflammation without prior priming (58). The activation of these metabolic gene programs is attributed to the increased binding of JUN to the target promoters (58). Considering that monocytes in acute myocarditis show altered JUN/FOS activity, along with changes in the metabolism-related gene pathway, further investigation is required to determine whether monocytes in acute myocarditis resemble monocyte-derived macrophages activated without prior priming.…”