Reduction of Heterogeneous nuclear ribonucleoprotein A1 levels in retinal pigment epithelial cells induces inflammation and inhibits autophagy flux: pathology of age-related macular degeneration.

Abstract

Heterogeneous nuclear ribonucleoprotein A1 (HNRNPA1) regulates RNA metabolism and inhibits various aging processes. It has also been reported as an inhibitor of inflammation; however, its role in the retina, particularly in retinal pigment epithelial (RPE) cells-a major source of inflammatory cytokines in the retina-remains unclear. Retinal inflammation is a key factor in the development of dry age-related macular degeneration (AMD), an age-related disease that can lead to blindness and currently lacks an established treatment. Therapeutic strategies are focused on preventing the suppression of autophagy, a precursor to inflammation. However, the factors regulating autophagy in RPE cells are not yet fully understood. In this study, we investigated the role of HNRNPA1 in RPE cells to evaluate its potential as a therapeutic target for dry AMD. HNRNPA1 knockdown experiments were conducted, followed by RNA sequencing (RNA-seq) and Gene Ontology term analyses to elucidate the impact of HNRNPA1 reduction. The results revealed that reduced HNRNPA1 levels induced the increased expression of CXCL8 and IL1B, decreased autolysosome formation, and increased autophagosome formation, showing that HNRNPA1 reduction induces inflammation and suppressed autophagy, demonstrating its essential role in maintaining autophagy and mitigating inflammation under normal conditions. Furthermore, in an NaIO3-induced dryAMD model, RPE degeneration was accompanied by a reduction in HNRNPA1. These findings raise the possibility that decreased HNRNPA1 levels play a role in the onset and progression of dry AMD, and support the rationale for further exploring HNRNPA1 as a potential therapeutic target for this currently untreatable condition.