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

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

Acknowledgements

We are grateful to Ms Kanno Sayaka for her technical assistance in this study.

Ethical approval and consent to participate

Ethical approval for this study (no. 29282) was provided by the Ethics Committee of Fukushima Medical University and written informed consent was obtained from each individual.

Conflict of interest

KM has received research grants from Chugai, Pfizer, and AbbVie and Eli Lilly. The rest of the authors declare that they have no competing interests.

Additional information

Funding

The study was supported by the Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED.