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

TL;DR

Reducing HNRNPA1 in retinal cells causes inflammation and blocks autophagy, which may contribute to the progression of dry age-related macular degeneration.

Contribution

This study identifies HNRNPA1 as a key regulator of autophagy and inflammation in retinal pigment epithelial cells, suggesting it as a potential therapeutic target for dry AMD.

Findings

HNRNPA1 knockdown increases inflammatory cytokines CXCL8 and IL1B in retinal pigment epithelial cells.

Reduced HNRNPA1 leads to autophagosome accumulation and decreased autolysosome formation, indicating suppressed autophagy flux.

Lower HNRNPA1 levels are observed in an NaIO3-induced dry AMD model, linking its reduction to disease progression.

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.

•HNRNPA1 knockdown triggers inflammation and inhibits autophagy in ARPE-19 cells.•HNRNPA1 reduction causes autophagosome accumulation, reduces autolysosome formation.•Autophagy flux inhibitor chloroquine induces inflammation in ARPE-19 cells.•HNRNPA1 is a potential therapeutic target for AMD.

HNRNPA1 knockdown triggers inflammation and inhibits autophagy in ARPE-19 cells.

HNRNPA1 reduction causes autophagosome accumulation, reduces autolysosome formation.

Autophagy flux inhibitor chloroquine induces inflammation in ARPE-19 cells.

HNRNPA1 is a potential therapeutic target for AMD.

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