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Uric acid-mediated inflammasome activation in IL-6 primed innate immune cells is regulated by baricitinib

Jumpei Temmoku¹, Yuya Fujita¹, Naoki Matsuoka¹

¹Department of Rheumatology, Fukushima Medical University School of Medicine, Fukushima, Japan.

Modern Rheumatology

|March 10, 2020

Abstract

Objectives:

Gout is an inflammatory arthropathy caused by the deposition of monosodium urate (MSU). The synthesis and release of IL-1β is crucial for MSU-induced synovial inflammation. The aim of the present study was to investigate the mechanism of MSU crystal-induced autoinflammatory processes.

Methods:

In vitro studies were used to evaluate the role of IL-6 in inflammasome activation in human neutrophils cultured with MSU crystals. Human neutrophils were stimulated with MSU in the presence or absence of IL-6 priming to determine NLRP3 inflammasome activation and subsequent cleaved caspase-1 induction or IL-1β production.

Results:

IL-6 or MSU stimulation alone did not result in the efficient IL-1β production from human neutrophils. However, MSU stimulation induced marked IL-1β production from IL-6-primed neutrophils. Pretreatment with baricitinib, which blocks IL-6 receptor signaling, prevented MSU-induced cleaved caspase-1 or IL-1β induction in IL-6-primed neutrophils. Tocilizumab pretreatment also inhibited MSU-mediated IL-1β production from IL-6-primed neutrophils.

Conclusion:

Priming of human neutrophils with IL-6 promotes uric acid-mediated IL-1β secretion in the absence of microbial stimulation. These results suggest that an endogenous cytokine, IL-6, is involved in MSU-mediated NLRP3 inflammasome activation and subsequent IL-1β production from innate immune cells and has a crucial role in MSU crystal-induced synovial inflammation. These findings provide insights into uric acid-mediated autoinflammation in the innate immune system.

Keywords:

Gout NLR family pyrin domain containing 3 inflammasome interleukin-1 beta interleukin-6 monosodium urate neutrophils

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