A research team at the Catholic University of Korea College of Medicine has recently identified a protein called Nuclear Receptor Coactivator 6 (NCOA6) as a potential inducer of gouty arthritis in joint macrophages, the primary cells responsible for innate immunity.
The team, led by Professor Kim Wan-uk of the Center for Integrative Rheumatoid Transcriptomics and Dynamics, found that NCOA6 interacts with the NLRP3 inflammasome – a protein complex believed to play a crucial role in initiating gouty arthritis.
Additionally, the research suggests that colchicine, a commonly used gout medication, may target NCOA6, hinting at a potential new avenue for gout treatment.
Gout is a metabolic disorder characterized by the accumulation of uric acid in the joints, with an approximate prevalence of 1 percent. Recent changes in dietary habits have led to a global increase in gout cases, prompting many patients to seek medical attention. Current treatments for gout focus on providing temporary relief from inflammation and pain, highlighting the urgent need for more fundamental therapeutic approaches.
Professor Kim's research team discovered an intriguing phenomenon where NCOA6, which typically remains inactive in the nucleus of macrophages, translocates to the cytoplasm upon stimulation.
The NLRP3 inflammasome is a protein complex crucial in the early stages of gouty arthritis, promoting the production of the inflammatory mediator interleukin-1β in response to uric acid accumulation in the joints.
However, master regulator controlling the activity of the NLRP3 inflammasome has remained unknown.
Through various cellular biology experiments, Professor Kim's team confirmed the physical interaction between cytoplasmic NCOA6 and the NLRP3 inflammasome. They also found that reducing NCOA6 levels in macrophages impaired interleukin-1β secretion even when the NLRP3 inflammasome was activated.
"Expanding upon these discoveries, the team established an animal model of gouty arthritis and observed a significant reduction in disease severity when NCOA6 protein was deficient.
Furthermore, they observed a substantial increase in NCOA6 expression in the affected joints of gouty arthritis patients and demonstrated that treatment with colchicine reduced NCOA6 levels in macrophages.
“We expect that this study will be a key resource for the diagnosis and treatment of not only gouty arthritis, but also rheumatoid arthritis, nephritis, cancer, and other diseases in which the NLRP3 inflammatory regulatory complex plays a major role in the pathogenesis,” Professor Kim said.
The research results were published in Cellular & Molecular Immunology.