Gout Risk Allele Regulating IRF5 Expression Is Associated with Enhanced IL-1β Production in Response to Palmitate and Monosodium Urate Crystals

TL;DR

A genetic variant linked to gout increases IL-1β production when immune cells are exposed to palmitate or urate crystals.

Contribution

The study identifies a functional mechanism by which a gout risk allele influences inflammation through IL-1β.

Findings

The rs4728141 C allele is associated with higher IL-1β in unstimulated control PBMCs.

IL-1β production is enhanced in C allele carriers when cells are stimulated with palmitate or monosodium urate crystals.

No link was found between the polymorphism and serum inflammatory proteome.

Abstract

Interferon Regulatory Factor 5 plays an important role in the regulation of innate immune responses by amplifying the Nuclear Factor κB response, which is critical in gout inflammation. Furthermore, the rs4728141 polymorphism C allele was associated with both increased IRF5 expression and susceptibility to gout. We examine the association between rs4728141 and cytokine production in response to various Toll-Like Receptor ligands and describe the transcriptomic and proteomic changes observed in patients with gout and controls in relation to this polymorphism. We examine the transcriptome of freshly isolated peripheral blood mononuclear cells (PBMCs) from 93 normouricemic donors and 63 gout patients as well as serum inflammatory proteome in 197 control and 195 gout samples. Stimulation experiments of freshly isolated human PBMCs were performed over 24 h, followed by RNA-sequencing in gout patients and cytokine production measurement by ELISA in normouricemic donors and gout patients. The rs4728141 C allele was associated with increased IL-1β expression in unstimulated PBMCs of controls, but not in gout. No association between the polymorphism and serum inflammatory proteome was found. As expected, an increased IRF5 expression was observed in stimulated PBMCs of rs4728141 C allele carriers in response to several stimulations. Interestingly, IL-1β production was specifically enhanced in association to the rs4728141 C allele when cells were stimulated with palmitate with or without monosodium urate crystals. This pattern of cytokine production shows a functional impact of rs4728141 in gout through altered IL-1β production.

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