The role of extracellular ASC in rheumatoid arthritis inflammation

Abstract

Rheumatoid Arthritis (RA) is a chronic autoinflammatory condition that affects 1% of the world´s population. It is a syndrome characterized by inflammation in the joints causing pain and disability. The pathogenesis of RA involves aberrant innate and adaptative immune responses. Several cytokines have been implicated in the pathogenesis and progression of the disease, with tumor-necrosis factor (TNF) and interleukin-1B (IL-1B) believed to be involved in perpetuating inflammatory processes in the joint. The innate immune system comprising at least three families of pattern recognition receptors (PRRs), the Toll-Like receptor (TLR), the Nod-like receptor (NLR or Inflammasome) and the RIG-like receptor (RLR) families is central in the disease processes in RA, promoting inflammation and amplifying the adaptative immune response. Although IL-1² is an important mediator of cartilage destruction in RA, very little is known about the role of inflammasomes in RA. The inflammasome is a cytosolic multiprotein oligomer that is responsible for the processing of pro- IL-1² and pro-IL-18. The inflammasome complex can consist of caspase-1 and ASC and NALP. Its activation is a two step mechanism that requires a first signal (signal 1) from another pattern recognition receptor in order to oligomerize with pro-caspase-1 and ASC and a subsequent second signal (signal 2) in order to process pro- IL-1² and pro-IL-18 into IL-1² and IL-18. Its regulation can lead to several inflammatory conditions, including Rheumatoid arthritis. One of hallmarks of inflammasome activation is the formation of an oligomeric structure called the "ASC-SPECK". This oligomeric structure is not only responsible for the processing of IL-1² and IL-18, but it has recently been shown to be secreted in the extracellular space propaging inflammation in nearby cells. ASC-SPECK have been found to be secreted in the extracellular space and has been detected in bodily fluids (such as BAL fluid, serum and even synovial fluid).Recent data generated at Butantan Institute using the AIRmax and AIRmin mice have demonstrated that AIRmin mice which carry a mutation in ASC protein (E19K), crucial for ASC-SPECK formation, are protected from RA. Therefore, it is our hypothesis that ASC-SPECK formation is crucial for the development of RA both from the aspect of inflammasome activation but most importantly for the propagation of inflammation via extracellular ASC-SPECK (Secreted ASC-SPECK). (AU)