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

doi:10.1016/j.celrep.2022.110942

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

Ophthalmology & Visual Neurosciences

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English (US)
Article number	110942
Journal	Cell reports
Volume	39
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2022.110942
State	Published - Jun 14 2022

Bibliographical note

Publisher Copyright:
© 2022 The Author(s)

Keywords

CP: Immunology
IL-1β
age-related macular degeneration
high fat diet
iron
macrophage
microglia
neuroinflammation
nutritional immunity
visceral adipose

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Sterling, J. K., Baumann, B., Foshe, S., Voigt, A., Guttha, S., Alnemri, A., McCright, S. J., Li, M., Zauhar, R. J., Montezuma, S. R., Kapphahn, R. J., Chavali, V. R. M., Hill, D. A., Ferrington, D. A., Stambolian, D., Mullins, R. F., Merrick, D., & Dunaief, J. L. (2022). Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction. Cell reports, 39(11), Article 110942. https://doi.org/10.1016/j.celrep.2022.110942

Sterling, JK, Baumann, B, Foshe, S, Voigt, A, Guttha, S, Alnemri, A, McCright, SJ, Li, M, Zauhar, RJ, Montezuma, SR, Kapphahn, RJ, Chavali, VRM, Hill, DA, Ferrington, DA, Stambolian, D, Mullins, RF, Merrick, D & Dunaief, JL 2022, 'Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction', Cell reports, vol. 39, no. 11, 110942. https://doi.org/10.1016/j.celrep.2022.110942

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abstract = "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.",

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AB - 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.

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Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

Abstract

Bibliographical note

Keywords

UN SDGs

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