The Role of Interleukin-17A and NLRP3 Inflammasome in the Pathogenesis of Graves’ Ophthalmopathy

Abstract

The development of Graves’ ophthalmopathy (GO) is associated with autoimmune dysfunction. Recent studies have indicated that IL-17A, inflammasomes, and related cytokines may be involved in the etiology of GO. We sought to investigate the pathogenic role of IL-17A and NLRP3 inflammasomes in GO. Orbital fat specimens were collected from 30 patients with GO and 30 non-GO controls. Immunohistochemical staining and orbital fibroblast cultures were conducted for both groups. IL-17A was added to the cell cultures, and cytokine expression, signaling pathways, and inflammasome mechanisms were investigated using reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, Western blotting, and small interfering RNA (siRNA) methods. Immunohistochemical staining showed higher NLRP3 expression in GO orbital tissue than in non-GO controls. IL-17A upregulated pro-IL-1β mRNA levels and IL-1β protein levels in the GO group. Furthermore, IL-17A was confirmed to enhance caspase-1 and NLRP3 protein expression in orbital fibroblasts, suggesting NLRP3 inflammasome activation. Inhibiting caspase-1 activity could also decrease IL-1β secretion. In siRNA-transfected orbital fibroblasts, significantly decreased NLRP3 expression was observed, and IL-17A-mediated pro-IL-1β mRNA release was also downregulated. Our observations illustrate that IL-17A promotes IL-1β production from orbital fibroblasts via the NLRP3 inflammasome in GO, and cytokines subsequently released may induce more inflammation and autoimmunity.