Molecules in the hippo pathway that regulate Th17 differentiation reveal the severity of ankylosing spondylitis

Abstract

Aim: Ankylosing spondylitis (AS) is a chronic, progressive, and inflammatory autoimmune disease of unknown origin that affects the axial skeleton and sacroiliac joints, resulting in pain and loss of function. AS is characterized by the overdifferentiation of T helper 17 (Th17) cells, which contribute to the development of the disease. The Hippo signaling pathway is an important regulator of Th17 differentiation, but its role in patients with AS is unclear. We aimed to investigate the role of key molecules of the Hippo signaling pathway in inflammatory Th17 differentiation in patients with AS and to examine their correlation with disease stages.

Methods: We examined the activity of the Hippo pathway in patients with AS and the regulation of Th17 differentiation during AS-mediated inflammation. Blood samples were collected from 60 patients with AS at various stages and 30 healthy controls. Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood by density gradient centrifugation. The Serum Interleukin-17 (IL-17) levels in patients with AS and healthy controls were quantified by ELISA. The key molecules of Hippo pathway were assessed by real-time PCR for their mRNA expression, and protein levels were determined by Western blot analysis.

Results: Elevated serum interleukin-17 (IL-17) levels were observed in patients with AS compared with healthy controls. The protein and mRNA levels of retinoic acid receptor-related orphan receptor γt (RORγt), transcriptional coactivator with a PDZ-binding motif (TAZ), and key upstream transcription factors in the Hippo signaling pathway were measured. The expression of RORγt and TAZ was increased in the blood of patients with AS, whereas the expression of other Hippo pathway proteins, such as MST1/2 and NDR1/2, was significantly decreased. Increased levels of IL-17 and TAZ were significantly associated with disease activity. In addition, MST1, MST2, and NDR1 levels were negatively correlated with TAZ, RORγt, and IL-17 levels.

Conclusion: Our findings suggest that the Hippo pathway plays a significant role in the regulation of Th17 differentiation and disease activity in patients with AS. The upregulation of TAZ and downregulation of key Hippo pathway proteins, such as MST1/2 and NDR1/2, may contribute to AS pathogenesis. These proteins may serve as biomarkers and may lead to the development of novel therapeutic strategies for AS.

Keywords: TAZ; ankylosing spondylitis; hippo signal pathway; inflammatory Th17 differentiation.