Monosodium urate crystals exposure is associated with limited transcriptional changes in primary human PBMCs.

Abstract

Introduction: Monosodium urate (MSU) crystals are the primary cause of gout, however the knowledge on MSU crystals exposure and inflammatory changes found in immune cells is diverse, with reports ranging from very limited inflammatory effects to substantial reprogramming of the cells induced by MSU crystals alone. We examine the IL-1β production patterns and the transcriptomic signature in response to MSU crystals alone or in combination with TLR ligands in freshly isolated primary human peripheral blood mononuclear cells (PBMCs).

Materials and methods: PBMCs were isolated by density gradient centrifugation and were stimulated for 24 hours with palmitate in the presence or absence of MSU crystals, followed by cytokine production measurement by ELISA. Two bulk RNA-sequencing analyses were performed independently following the same experimental conditions using PBMCs of patients with gout stimulated with medium control, palmitate and LPS in the presence or absence of MSU crystals.

Results: MSU crystals alone induced a small but significant increase in IL-1β production in human PBMCs. IL-1β production was significantly increased when PBMCs were stimulated with palmitate and this was further amplified by the palmitate-MSU combination. Of high interest, MSU crystals alone or in combination with other stimuli caused no significant transcriptomic alterations.

Conclusions: We confirm the synergistic effect of MSU crystals with palmitate that leads to higher IL-1β production. Transcriptomic analysis shows that MSU crystal exposure is not associated with major transcriptional changes in PBMCs. This suggests that the production of IL-1β in response to MSU crystals may largely be regulated at the post-transcriptional level and additional synergistic stimuli are likely required to fully explain the inflammatory response observed clinically in gout. Moreover, this could also bear relevance for other metabolic disorders associated to hyperuricemia where asymptomatic MSU crystal deposition may be present.