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 Jayagopal; J. Samuel Zigler; Swaminathan Sethu; James T. Handa; Simon C. Watkins; Arkasubhra Ghosh; Debasish Sinha

doi:10.1038/s42003-019-0588-y

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 journal › Article › peer-review

9 Scopus citations

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 language	English (US)
Article number	348
Journal	Communications biology
Volume	2
Issue number	1
DOIs	https://doi.org/10.1038/s42003-019-0588-y
State	Published - Dec 1 2019

ASJC Scopus subject areas

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

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Ghosh, S., Padmanabhan, A., Vaidya, T., Watson, A. M., Bhutto, I. A., Hose, S., Shang, P., Stepicheva, N., Yazdankhah, M., Weiss, J., Das, M., Gopikrishna, S., Aishwarya, Yadav, N., Berger, T., Mak, T. W., Xia, S., Qian, J., Lutty, G. A., ... Sinha, D. (2019). Neutrophils homing into the retina trigger pathology in early age-related macular degeneration. Communications biology, 2(1), Article 348. https://doi.org/10.1038/s42003-019-0588-y

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

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title = "Neutrophils homing into the retina trigger pathology in early age-related macular degeneration",

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.",

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

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AU - Ghosh, Sayan

AU - Padmanabhan, Archana

AU - Vaidya, Tanuja

AU - Watson, Alan M.

AU - Bhutto, Imran A.

AU - Hose, Stacey

AU - Shang, Peng

AU - Stepicheva, Nadezda

AU - Yazdankhah, Meysam

AU - Weiss, Joseph

AU - Das, Manjula

AU - Gopikrishna, Santosh

AU - Aishwarya,

AU - Yadav, Naresh

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

PY - 2019/12/1

Y1 - 2019/12/1

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.

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

Abstract

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