Current understanding of the role of inflammasome activation in the pathophysiology of systemic Juvenile Idiopathic Arthritis

Abstract

Systemic Juvenile Idiopathic Arthritis (sJIA) is a severe disease with autoinflammatory characteristics that mainly affects young children. It is characterised by systemic inflammation and fever. sJIA patients have elevated levels of the proinflammatory cytokines interleukin (IL)-1β, IL-6, and IL-18 with elevated levels of S100A8/A9, S100A12, and the acute-phase protein ferritin. Approximately 10% of the children with sJIA also develop the life-threatening complication macrophage activation syndrome (MAS), which comes with fever and very high levels of ferritin. sJIA patients are treated with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and biologicals that block the IL-1 and IL-6 pathway. The exact cause of the disease remains unknown but the inflammasome likely plays an important role in the pathophysiology. IL-1β and IL-18 both are products of an activated inflammasome and S100A8/A9, S100A12, and ferritin are associated with inflammasome activation. Furthermore, gain-of-function mutations in the nucleotide-binding domain of nucleotide-binding oligomerization domain leucine-rich repeat receptor (NLR) caspase activation and recruitment domain (CARD) containing 4 (NLRC4) inflammasome are associated with MAS. This review focuses on the current understanding of the possible role of the five best understood inflammasomes (NLR pyrin domain containing 1 (NLRP1), NLRP3, NLRC4, absent in melanoma 2 (AIM2), and pyrin) in the pathophysiology of sJIA. This knowledge is important for future research into the treatment and possible prevention of sJIA. Direct research into the role of the different inflammasomes in sJIA is scarce and therefore the symptoms, cytokine expression and treatments of monogenic autoinflammatory disorders as a comparison to sJIA will also be used to determine the likelihood of the involvement of the respective inflammasome in sJIA pathophysiology. Data of studies focussing on inflammasomes in sJIA and the comparisons with inflammasomopathies, indicate that the NLRC4 and AIM2 inflammasome are most likely involved in the pathophysiology of sJIA.