Neutrophils homing into the retina trigger pathology in early age-related macular degeneration.
Aged
Aged, 80 and over
Animals
Biomarkers
Disease Models, Animal
Female
Gene Expression
Humans
Immunophenotyping
Interferon-gamma
/ metabolism
Lipocalin-2
/ genetics
Macular Degeneration
/ etiology
Male
Mice
Mice, Knockout
Models, Biological
Neutrophil Infiltration
Neutrophils
/ immunology
Proto-Oncogene Proteins c-akt
/ antagonists & inhibitors
Reactive Oxygen Species
/ metabolism
Retina
/ immunology
Ageing
Interferons
Mechanisms of disease
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
2019
2019
Historique:
received:
18
02
2019
accepted:
27
08
2019
entrez:
26
9
2019
pubmed:
26
9
2019
medline:
26
9
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31552301
doi: 10.1038/s42003-019-0588-y
pii: 588
pmc: PMC6754381
doi:
Substances chimiques
Biomarkers
0
LCN2 protein, human
0
Lipocalin-2
0
Reactive Oxygen Species
0
Interferon-gamma
82115-62-6
AKT2 protein, human
EC 2.7.11.1
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
348Subventions
Organisme : NEI NIH HHS
ID : P30 EY008098
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY016151
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY019037
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY027691
Pays : United States
Déclaration de conflit d'intérêts
Competing interestsA.J. and D.S. are inventors in a US patent filed by F. Hoffmann-La Roche, Ltd., Basel, Switzerland on an AKT2 inhibitor for treatment of dry AMD. The remianing authors declare no competing interests.
Références
Blood. 2017 Mar 9;129(10):1357-1367
pubmed: 28073784
Front Physiol. 2018 Feb 20;9:113
pubmed: 29515456
Thromb Haemost. 2014 Oct;112(4):659-65
pubmed: 25265341
Proc Natl Acad Sci U S A. 2015 Sep 1;112(35):10950-5
pubmed: 26269569
Aging Cell. 2017 Apr;16(2):349-359
pubmed: 28083894
Prog Retin Eye Res. 2009 Jan;28(1):1-18
pubmed: 19026761
Shock. 2012 Aug;38(3):281-7
pubmed: 22683734
Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2371-2380
pubmed: 29847643
J Invest Dermatol. 2016 Jul;136(7):1418-1428
pubmed: 26979478
J Pathol. 2017 Apr;241(5):583-588
pubmed: 28026019
Nat Med. 2015 Aug;21(8):880-6
pubmed: 26214837
J Biol Chem. 2004 Oct 1;279(40):42279-89
pubmed: 15280374
Adv Protein Chem Struct Biol. 2012;88:69-132
pubmed: 22814707
Alzheimers Dement (N Y). 2018 Sep 06;4:575-590
pubmed: 30406177
PLoS One. 2015 Mar 20;10(3):e0120415
pubmed: 25793273
Biochim Biophys Acta. 2015 Oct;1853(10 Pt A):2240-50
pubmed: 26190820
Br J Cancer. 2017 Jul 11;117(2):159-163
pubmed: 28557977
J Invest Surg. 2004 Sep-Oct;17(5):239-47
pubmed: 15385257
PLoS One. 2017 Jul 7;12(7):e0180486
pubmed: 28686653
Exp Eye Res. 2005 Mar;80(3):323-35
pubmed: 15721615
FASEB J. 2017 Nov;31(11):4903-4916
pubmed: 28729290
J Cell Biol. 2010 Nov 1;191(3):677-91
pubmed: 20974816
Glia. 2007 Jul;55(9):942-53
pubmed: 17457855
Autophagy. 2014 Mar;10(3):480-96
pubmed: 24468901
Biomarkers. 2015;20(8):565-71
pubmed: 26671823
Nat Commun. 2018 Nov 14;9(1):4777
pubmed: 30429468
Mol Cancer Ther. 2011 Feb;10(2):360-71
pubmed: 21191045
Nat Methods. 2007 Apr;4(4):331-6
pubmed: 17384643
Exp Cell Res. 1992 Jun;200(2):272-84
pubmed: 1374036
Am J Ophthalmol. 2001 Nov;132(5):668-81
pubmed: 11704028
J Vis Exp. 2018 Mar 16;(133):
pubmed: 29608155
EMBO J. 2002 Feb 1;21(3):211-20
pubmed: 11823414
Ophthalmology. 2013 Aug;120(8):1604-11.e4
pubmed: 23582353
Nat Immunol. 2017 Oct;18(10):1084-1093
pubmed: 28846084
Mol Cancer Res. 2015 Dec;13(12):1602-14
pubmed: 26374334
Immun Ageing. 2017 Jul 27;14:18
pubmed: 28769990
Pharmacol Ther. 2017 Apr;172:101-115
pubmed: 27919797
Clin Cancer Res. 2017 Nov 15;23(22):6823-6832
pubmed: 28874413
BMC Ophthalmol. 2018 May 30;18(1):130
pubmed: 29843663
Arch Ophthalmol. 2001 Oct;119(10):1417-36
pubmed: 11594942
Proc Natl Acad Sci U S A. 2016 Sep 20;113(38):10678-83
pubmed: 27601663
Br J Ophthalmol. 2003 Sep;87(9):1159-66
pubmed: 12928288
Exp Eye Res. 2014 Mar;120:61-70
pubmed: 24462632
Invest Ophthalmol Vis Sci. 2018 Mar 20;59(4):AMD104-AMD113
pubmed: 30098172
Eur J Immunol. 2012 Dec;42(12):3346-57
pubmed: 22965758
Clin Exp Immunol. 2009 Mar;155(3):559-66
pubmed: 19077082
Blood. 2005 Jul 15;106(2):584-92
pubmed: 15811956
Nat Rev Immunol. 2013 Jun;13(6):438-51
pubmed: 23702979
Invest Ophthalmol Vis Sci. 2018 Mar 20;59(4):AMD83-AMD92
pubmed: 30025105
Prog Retin Eye Res. 2016 Sep;54:64-102
pubmed: 27156982
J Immunol Res. 2017;2017:9748345
pubmed: 29238732
Prog Retin Eye Res. 2019 May;70:85-98
pubmed: 30552975
J Biol Chem. 2017 Jan 13;292(2):435-445
pubmed: 27920206
Aging Cell. 2014 Dec;13(6):1091-4
pubmed: 25257511
Blood. 2014 Dec 4;124(24):3515-23
pubmed: 25278585
Nat Methods. 2008 Jul;5(7):621-8
pubmed: 18516045
Cell. 2017 Apr 20;169(3):381-405
pubmed: 28431241
J Cell Sci. 2009 Jan 15;122(Pt 2):268-77
pubmed: 19118219
Mol Aspects Med. 2012 Aug;33(4):487-509
pubmed: 22705444
Proc Natl Acad Sci U S A. 2006 Feb 7;103(6):1834-9
pubmed: 16446425
Mol Metab. 2013 May 09;2(3):161-70
pubmed: 24049731
J Immunol. 2018 May 15;200(10):3364-3371
pubmed: 29632142
EMBO Mol Med. 2018 Oct;10(10):
pubmed: 30224384
Hepatology. 2018 Oct;68(4):1347-1360
pubmed: 29631332
Cancer Biol Ther. 2008 Jul;7(7):1109-15
pubmed: 18698163
Cell Signal. 2015 Jul;27(7):1398-412
pubmed: 25819340
Wiley Interdiscip Rev Syst Biol Med. 2009 Nov-Dec;1(3):309-333
pubmed: 20836000
J Immunol. 2001 Jun 1;166(11):6795-801
pubmed: 11359838
Cell Adh Migr. 2013 Nov-Dec;7(6):476-81
pubmed: 24430200
Exp Eye Res. 2006 May;82(5):741-52
pubmed: 16325179
Sci Rep. 2017 Jun 12;7(1):3222
pubmed: 28607377
BMJ Open. 2013 Nov 07;3(11):e003471
pubmed: 24202057
Curr Opin Hematol. 2016 Jan;23(1):36-43
pubmed: 26554893
J Cell Biol. 2009 Jul 13;186(1):99-111
pubmed: 19581412
Lancet Oncol. 2017 Oct;18(10):1360-1372
pubmed: 28800861
Open Biol. 2012 Nov;2(11):120134
pubmed: 23226600