Pathophysiologic role of Interleukin-33/ST2 in Sjogren's syndrome

Interleukin-33 (IL-33) is a member of the IL-1 family and has dual functions as a nuclear factor as well as a cytokine. The pivotal role of IL-33 as an active player contributing to aberrant local and systemic damage has been highlighted in several inflammatory and autoimmune diseases. Primary Sjogren's syndrome (pSS) is an autoimmune disease characterized by dry eyes and mouth syndrome due to local dysfunctions of exocrine glands, but also accompanied with systemic manifestations. The pathophysiology of pSS has been advocated as a conjecture of activated B and T cells as well as the production of inflammatory cytokines and autoantibodies, driving epithelial tissue damage and disease progression. In pSS, IL-33 is released in the extracellular space from damaged salivary cells upon pro-inflammatory stimuli and/or dysfunction of epithelial barrier. Counter-regulatory mechanisms are initiated to limit the pro-inflammatory actions of IL-33 as portrayed by an increase in the decoy receptor for IL-33, the soluble form of ST2 (sST2). In pSS and associated diseases, the levels of IL-33 are significantly elevated in the serum or tears of patients. Mechanistically, IL-33 acts in synergy with IL-12 and IL-23 on NK and NKT cells to boost the production of IFN-gamma contributing to inflammation. TNF-alpha, IL-1 beta and IFN-gamma in turn further increase the activation of IL-33/ST2 pathway, thereby constituting a vicious inflammatory loop leading to disease exacerbation. IL-33/ST2 axis is involved in Sjogren's syndrome and opens new perspectives as therapeutic target of one of the culprits in the inflammatory perpetuation.

Automated summary

IL-33 plays a crucial role in Sjogren's syndrome by contributing to inflammation and interacting with other cytokines to exacerbate the disease progression.