Deficiency of antioxidant enzyme PRDX6 and mucosal chemokine CXCL17: unraveling the factors behind oxidative stress and mucosal homeostasis disruption in dry eye disease

This study aimed to identify dysregulated proteins in Schirmer strip samples (ScS) from Sjögren's syndrome dry eye (SSDE) patients to uncover key biological processes using untargeted proteomics. The focus then shifted to two dysregulated proteins, PRDX6 and CXCL17, due to their roles in oxidative stress and mucosal immunity, with the goal of exploring their potential as therapeutic targets. Their involvement was further investigated in vitro and validated in a larger SSDE cohort, assessing their relationship with clinical signs. ScS from 12 SSDE patients and 6 healthy controls underwent untargeted proteomic analysis. PRDX6 and CXCL17 levels in ScS from 39 SSDE patients were quantified using ELISA. In vitro, human corneal epithelial cells (HCEc) were exposed to hyperosmolarity or IFN-γ, and PRDX6 and CXCL17 expression was assessed by RT-qPCR for gene expression and by ELISA and immunocytochemistry for protein expression. Untargeted proteomics identified 111 dysregulated proteins in SSDE, highlighting alterations in oxidative stress, cell metabolism, cytoskeleton organization, and programmed cell death. Targeted proteomics showed positive correlations between PRDX6 levels and TBUT/Schirmer tests, and negative correlations with OSDI/Oxford scores. CXCL17 levels negatively correlated with the Oxford score. In vitro, PRDX6 and CXCL17 expression increased under hyperosmotic or inflammatory stress, displaying inverse trends compared to ScS from SSDE patients. This study elucidates the biological processes driving epithelial cell alterations in SSDE, focusing on oxidative stress and mucosal homeostasis. It underscores the significant roles of PRDX6 and CXCL17 in these processes, suggesting their potential as biomarkers or therapeutic targets for SSDE.