Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction
Jacob K. Sterling,
Bailey Baumann,
Sierra Foshe,
Andrew Voigt,
Samyuktha Guttha,
Ahab Alnemri,
Sam J. McCright,
Mingyao Li,
Randy J. Zauhar,
Sandra R. Montezuma,
Rebecca J. Kapphahn,
Venkata R.M. Chavali,
David A. Hill,
Deborah A. Ferrington,
Dwight Stambolian,
Robert F. Mullins,
David Merrick,
Joshua L. Dunaief
Affiliations
Jacob K. Sterling
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Medical Scientist Training Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Bailey Baumann
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Medical Scientist Training Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Sierra Foshe
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Andrew Voigt
Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
Samyuktha Guttha
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Ahab Alnemri
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Sam J. McCright
Medical Scientist Training Program, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA
Mingyao Li
Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Randy J. Zauhar
Department of Chemistry & Biochemistry, University of the Sciences, Philadelphia, PA 19104, USA
Sandra R. Montezuma
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA
Rebecca J. Kapphahn
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA
Venkata R.M. Chavali
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
David A. Hill
Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Deborah A. Ferrington
Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA
Dwight Stambolian
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Robert F. Mullins
Institute for Vision Research, The University of Iowa, Iowa City, IA 52242, USA; Department of Ophthalmology and Visual Sciences, The University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA
David Merrick
Department of Medicine, Division of Endocrinology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Institute of Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA
Joshua L. Dunaief
FM Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA; Corresponding author
Summary: 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.
