Neutrophils homing into the retina trigger pathology in early age-related macular degeneration

Sayan Ghosh, Archana Padmanabhan, Tanuja Vaidya, Alan M. Watson, Imran A. Bhutto, Stacey Hose, Peng Shang, Nadezda Stepicheva, Meysam Yazdankhah, Joseph Weiss, Manjula Das, Santosh Gopikrishna, Aishwarya, Naresh Yadav, Thorsten Berger, Tak W. Mak, Shuli Xia, Jiang Qian, Gerard A. Lutty, Ashwath JayagopalJ. Samuel Zigler, Swaminathan Sethu, James T. Handa, Simon C. Watkins, Arkasubhra Ghosh, Debasish Sinha

Research output: Contribution to journalArticle

Abstract

Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ− activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD.

Original languageEnglish (US)
Article number348
JournalCommunications Biology
Volume2
Issue number1
DOIs
StatePublished - Dec 1 2019

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Lipocalins
Macular Degeneration
Pathology
retina
Infiltration
Retina
neutrophils
Neutrophils
Neutrophil Infiltration
Confocal microscopy
Integrins
inflammation
animal models
Coloring Agents
Adhesion
Inflammation
Phenotype
Chemical activation
phenotype
Neutrophil Activation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • Medicine (miscellaneous)

Cite this

Neutrophils homing into the retina trigger pathology in early age-related macular degeneration. / Ghosh, Sayan; Padmanabhan, Archana; Vaidya, Tanuja; Watson, Alan M.; Bhutto, Imran A.; Hose, Stacey; Shang, Peng; Stepicheva, Nadezda; Yazdankhah, Meysam; Weiss, Joseph; Das, Manjula; Gopikrishna, Santosh; Aishwarya; Yadav, Naresh; Berger, Thorsten; Mak, Tak W.; Xia, Shuli; Qian, Jiang; Lutty, Gerard A.; Jayagopal, Ashwath; Zigler, J. Samuel; Sethu, Swaminathan; Handa, James T.; Watkins, Simon C.; Ghosh, Arkasubhra; Sinha, Debasish.

In: Communications Biology, Vol. 2, No. 1, 348, 01.12.2019.

Research output: Contribution to journalArticle

Ghosh, S, Padmanabhan, A, Vaidya, T, Watson, AM, Bhutto, IA, Hose, S, Shang, P, Stepicheva, N, Yazdankhah, M, Weiss, J, Das, M, Gopikrishna, S, Aishwarya, Yadav, N, Berger, T, Mak, TW, Xia, S, Qian, J, Lutty, GA, Jayagopal, A, Zigler, JS, Sethu, S, Handa, JT, Watkins, SC, Ghosh, A & Sinha, D 2019, 'Neutrophils homing into the retina trigger pathology in early age-related macular degeneration', Communications Biology, vol. 2, no. 1, 348. https://doi.org/10.1038/s42003-019-0588-y
Ghosh, Sayan ; Padmanabhan, Archana ; Vaidya, Tanuja ; Watson, Alan M. ; Bhutto, Imran A. ; Hose, Stacey ; Shang, Peng ; Stepicheva, Nadezda ; Yazdankhah, Meysam ; Weiss, Joseph ; Das, Manjula ; Gopikrishna, Santosh ; Aishwarya ; Yadav, Naresh ; Berger, Thorsten ; Mak, Tak W. ; Xia, Shuli ; Qian, Jiang ; Lutty, Gerard A. ; Jayagopal, Ashwath ; Zigler, J. Samuel ; Sethu, Swaminathan ; Handa, James T. ; Watkins, Simon C. ; Ghosh, Arkasubhra ; Sinha, Debasish. / Neutrophils homing into the retina trigger pathology in early age-related macular degeneration. In: Communications Biology. 2019 ; Vol. 2, No. 1.
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AU - Padmanabhan, Archana

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AU - Bhutto, Imran A.

AU - Hose, Stacey

AU - Shang, Peng

AU - Stepicheva, Nadezda

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AU - Berger, Thorsten

AU - Mak, Tak W.

AU - Xia, Shuli

AU - Qian, Jiang

AU - Lutty, Gerard A.

AU - Jayagopal, Ashwath

AU - Zigler, J. Samuel

AU - Sethu, Swaminathan

AU - Handa, James T.

AU - Watkins, Simon C.

AU - Ghosh, Arkasubhra

AU - Sinha, Debasish

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N2 - Age-related macular degeneration (AMD) is an expanding problem as longevity increases worldwide. While inflammation clearly contributes to vision loss in AMD, the mechanism remains controversial. Here we show that neutrophils are important in this inflammatory process. In the retinas of both early AMD patients and in a mouse model with an early AMD-like phenotype, we show neutrophil infiltration. Such infiltration was confirmed experimentally using ribbon-scanning confocal microscopy (RSCM) and IFNλ− activated dye labeled normal neutrophils. With neutrophils lacking lipocalin-2 (LCN-2), infiltration was greatly reduced. Further, increased levels of IFNλ in early AMD trigger neutrophil activation and LCN-2 upregulation. LCN-2 promotes inflammation by modulating integrin β1 levels to stimulate adhesion and transmigration of activated neutrophils into the retina. We show that in the mouse model, inhibiting AKT2 neutralizes IFNλ inflammatory signals, reduces LCN-2-mediated neutrophil infiltration, and reverses early AMD-like phenotype changes. Thus, AKT2 inhibitors may have therapeutic potential in early, dry AMD.

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