JAM-C prevents ocular fibrosis by suppressing the TAZ/KLF6 pathway.

Abstract

INTRODUCTION: Ocular fibrosis is one of the leading causes of irreversible visual impairment or blindness. Currently, there is no effective drug available for such diseases. Therefore, understanding the underlying mechanisms is a prerequisite for finding better therapeutic strategies. OBJECTIVES: This study aims to investigate the role of the junctional adhesion molecule C (JAM-C) in ocular fibrosis. METHODS: The protein levels of JAM-C were determined in the vitreous humor samples of patients with ocular fibrosis using ELISA. Jam-c genetic deletion mice and ocular fibrosis mouse models were generated to study the role of JAM-C in vivo. EMT, proliferation, migration, and gel contraction capacities in RPE cells were examined after JAM-C knockdown by siRNAs. RNA sequencing, co-IP, ChIP-qPCR, and luciferase reporter assay were performed to investigate the underlying mechanisms. Subretinal injection of adeno-associated virus, immunofluorescence, western blot were performed to evaluate the potential of JAM-C in preventing ocular fibrosis in different mouse models. RESULTS: Markedly reduced JAM-C expression was found in patients with ocular fibrosis. Genetic deletion of Jam-c in mice exacerbated ocular fibrosis, and JAM-C knockdown triggered the EMT process in RPE cells. Mechanistically, we reveal that JAM-C inhibits ocular fibrosis by suppressing the nuclear localization and function of TAZ, which otherwise binds to KLF6 to promote its expression and activity to initiate the EMT cascade. Importantly, AAV-mediated JAM-C augmentation alleviated ocular fibrosis in different mouse models. CONCLUSION: Our findings unveil a novel function of JAM-C in preventing ocular fibrosis by inhibiting the TAZ/KLF6 pathway, and suggest new therapeutic possibilities for the treatment of fibrotic diseases.