Gout Risk Allele Regulating <em>IRF5</em> Expression is Associated with Enhanced IL-1β Production in Response to Palmitate and Monosodium Urate Crystals

Background 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. Materials and Methods We examine the transcriptome of freshly isolated peripheral blood mononuclear cells (PBMCs) from 93 healthy donors and 63 gout patients as well as serum inflammatory proteome in 197 control and 195 gout samples. 24-hour stimulation experiments of freshly isolated human PBMCs were performed, followed by RNA-sequencing in gout patients and cytokine production measurement by ELISA in healthy donors and gout patients. Results 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. Conclusions The recently identified gout risk allele C rs4728141, which maps to the vicinity to the IRF5 gene is associated with elevated proinflammatory responses and this was specifically observed in response to gout-relevant stimulations such as palmitate in presence or absence of monosodium urate crystals. This pattern of cytokine production shows a functional impact of rs4728141 in gout through altered IL-1β production, a main driver of inflammation in gout.