We demonstrate that TNF‐α, secreted from activated Mos, mediates downregulation of OTX2 and essential RPE genes such as RDH5. Our data show how subretinal, chronic inflammation can affect RPE function, which likely contributes to the visual dysfunctions and later degeneration in diseases such as AMD where subretinal Mφs are observed. This evidence concerns the gene OTX2 and age-related macular degeneration.