Old Disease, New Tricks: A Novel Approach to Understanding Gout

SAN DIEGO—Gout has sometimes been called the disease of kings, not only because of the fact that purine-rich foods were long affordable only to wealthier individuals, but also because the disease has been around since the monarchies that existed centuries ago. However, with groundbreaking research leading to a better understanding of gout, we can now see this disease in a different light than in ages past. At the session titled, The Word Is Out: New Mechanisms and Targets of Gout, several paradigm-shifting ideas were put forth by two esteemed researchers on this subject.

Inflammasomes & the Pathophysiology of Gout

Ali Abdul-Sater, PhD Photo: York University, Toronto

The first speaker was Ali Abdul-Sater, PhD, associate professor in the faculty of health, York University, Toronto. To explain the work being undertaken in Dr. Abdul-Sater’s lab, it is first important to understand the concept of the inflammasome and how this relates to the pathophysiology of gout.

Inflammasomes are innate immune system receptors and sensors that are involved in the promulgation and regulation of caspase-1 and become more active in response to infectious microbes and molecules from host proteins.¹ The concept of the inflammasome is relevant in gout given that, in acute flares, monosodium urate (MSU) crystals are engulfed by resident synovial macrophages, which in turn activate the NLRP3 inflammasome. Interleukin-1 (IL-1) beta is subsequently released into the joint space and into the systemic circulation. Neutrophils can then proliferate, enter the joint and engulf MSU crystals. This process results in joint pain and swelling.

With this context in mind, Dr. Abdul-Sater explained that dysregulation of inflammasomes, such as NLRP3, has been implicated in inflammatory arthritides, such as gout. Further, that tight regulation of this inflammasome may be important in preventing disease. Tumor necrosis factor receptor-associated factor 1 (TRAF1) is a signaling adapter that can participate in this type of regulation. TRAF1 has been linked to a heightened risk of inflammatory arthritis, such as with rheumatoid arthritis.

Because the linear ubiquitin chain assembly complex helps regulate the NLRP3 inflammasome and because TRAF1 participates in the sequestration of the linear ubiquitin assembly complex known as LUBAC, Dr. Abdul-Sater and colleagues speculated that TRAF1 may help control NLRP3 inflammasome activation.  They demonstrated that TRAF1 knockout mice exhibit increased inflammatory cell recruitment in an NLRP3 inflammasome in vivo model, and these mice are more susceptible to MSU crystal-induced gout. In addition, this team showed that targeting the TRAF1/cIAP2 axis lowers inflammation and IL-1beta production.