Age-related macular degeneration (AMD), the leading cause of irreversible blindness among Americans over 50, is characterized by dysfunction and death of retinal pigment epithelial (RPE) cells. The RPE accumulates iron in AMD, and iron overload triggers RPE cell death in vitro and in vivo. However, the mechanism of RPE iron accumulation in AMD is unknown. We show that high-fat-diet-induced obesity, a risk factor for AMD, drives systemic and local inflammatory circuits upregulating interleukin-1β (IL-1β). IL-1β upregulates RPE iron importers and downregulates iron exporters, causing iron accumulation, oxidative stress, and dysfunction. We term this maladaptive, chronic activation of a nutritional immunity pathway the cellular iron sequestration response (CISR). RNA sequencing (RNA-seq) analysis of choroid and retina from human donors revealed that hallmarks of this pathway are present in AMD microglia and macrophages. Together, these data suggest that inflamed adipose tissue, through the CISR, can lead to RPE pathology in AMD.
Bibliographical noteFunding Information:
Funding for J.K.S. was provided by the National Institutes of Health /National Eye Institute ( F30EY032339 ). Funding for J.K.S., B.B., S.F., S.G., A.A., and J.L.D. was provided by the National Institutes of Health/ National Eye Institute ( R01EY028916 ), Research to Prevent Blindness, the FM Kirby Foundation , the Paul and Evanina Bell Mackall Foundation Trust , and a gift in memory of Lee F. Mauger, MD. Funding for S.F. was provided by Graduate Training in Neuroscience ( T32NS105607 ). Funding for S.J.M. was provided by the Michael Brown Fellowship . Funding for D.A.H. and S.J.M. was provided by the National Institutes of Health ( K08 DK116668 ). Funding for S.R.M., R.J.K., and D.A.F. was provided by the National Institutes of Health/National Eye Institute ( R01EY026012 ), Elaine and Robert Larson Endowed Vision Research Chair and Helen Lindsay Family Foundation , and the Knobloch Chair Professorship . Funding for V.R.M.C. was provided by the National Institutes of Health/National Eye Institute ( R21EY028273 ). Funding for M.L. was provided by the National Institutes of Health/National Eye Institute ( R01EY030192 , R21EY031877 , and R01EY031209 ). Funding for D.S. was provided by the National Institutes of Health/National Eye Institute ( R01EY031209 ). Funding for D.M. was provided by the National Institutes of Health/ National Institute of Diabetes and Digestive and Kidney Disease ( K08DK122099 ).
© 2022 The Author(s)
- age-related macular degeneration
- CP: Immunology
- high fat diet
- nutritional immunity
- visceral adipose
PubMed: MeSH publication types
- Journal Article
- Research Support, N.I.H., Extramural