4.8 Article

Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

期刊

CELL REPORTS
卷 39, 期 11, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.celrep.2022.110942

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资金

  1. National Institutes of Health/National Eye Institute [R01EY031209, F30EY032339, R01EY028916, R21EY028273, R01EY030192, R21EY031877, K08DK122099]
  2. Research to Prevent Blindness
  3. FM Kirby Foundation
  4. Paul and Evanina Bell Mackall Foundation Trust
  5. Graduate Training in Neuroscience [T32NS105607]
  6. Michael Brown Fellowship
  7. National Institutes of Health [K08 DK116668]
  8. Elaine and Robert Larson Endowed Vision Research Chair and Helen Lindsay Family Foundation
  9. Knobloch Chair Professorship

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This study reveals that obesity induced by a high-fat diet can lead to inflammation in AMD, which in turn triggers iron accumulation and dysfunction in RPE cells.
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-1 beta (IL-1 beta). IL-1 beta 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.

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