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

13 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

Funding 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 ).

Publisher Copyright:
© 2022 The Author(s)

Keywords

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

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural

UN SDGs

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

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10.1016/j.celrep.2022.110942

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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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title = "Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction",

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.",

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

author = "Sterling, {Jacob K.} and Bailey Baumann and Sierra Foshe and Andrew Voigt and Samyuktha Guttha and Ahab Alnemri and McCright, {Sam J.} and Mingyao Li and Zauhar, {Randy J.} and Montezuma, {Sandra R.} and Kapphahn, {Rebecca J.} and Chavali, {Venkata R.M.} and Hill, {David A.} and Ferrington, {Deborah A.} and Dwight Stambolian and Mullins, {Robert F.} and David Merrick and Dunaief, {Joshua L.}",

note = "Funding 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 ). Publisher Copyright: {\textcopyright} 2022 The Author(s)",

year = "2022",

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doi = "10.1016/j.celrep.2022.110942",

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T1 - Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

AU - Sterling, Jacob K.

AU - Baumann, Bailey

AU - Foshe, Sierra

AU - Voigt, Andrew

AU - Guttha, Samyuktha

AU - Alnemri, Ahab

AU - McCright, Sam J.

AU - Li, Mingyao

AU - Zauhar, Randy J.

AU - Montezuma, Sandra R.

AU - Kapphahn, Rebecca J.

AU - Chavali, Venkata R.M.

AU - Hill, David A.

AU - Ferrington, Deborah A.

AU - Stambolian, Dwight

AU - Mullins, Robert F.

AU - Merrick, David

AU - Dunaief, Joshua L.

N1 - Funding 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 ). Publisher Copyright: © 2022 The Author(s)

PY - 2022/6/14

Y1 - 2022/6/14

N2 - 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.

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.

KW - age-related macular degeneration

KW - CP: Immunology

KW - high fat diet

KW - IL-1β

KW - iron

KW - macrophage

KW - microglia

KW - neuroinflammation

KW - nutritional immunity

KW - visceral adipose

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SN - 2211-1247

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JF - Cell reports

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ER -

Inflammatory adipose activates a nutritional immunity pathway leading to retinal dysfunction

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

Publisher link

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