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Article ; Online: HIF1α-dependent hypoxia response in myeloid cells requires IRE1α.

Mawambo, Gaëlle / Oubaha, Malika / Ichiyama, Yusuke / Blot, Guillaume / Crespo-Garcia, Sergio / Dejda, Agnieszka / Binet, François / Diaz-Marin, Roberto / Sawchyn, Christina / Sergeev, Mikhail / Juneau, Rachel / Kaufman, Randal J / Affar, El Bachir / Mallette, Frédérick A / Wilson, Ariel M / Sapieha, Przemyslaw

Journal of neuroinflammation

2023 Volume 20, Issue 1, Page(s) 145

Abstract: Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to ... ...

Abstract	Cellular adaptation to low oxygen tension triggers primitive pathways that ensure proper cell function. Conditions of hypoxia and low glucose are characteristic of injured tissues and hence successive waves of inflammatory cells must be suited to function under low oxygen tension and metabolic stress. While Hypoxia-Inducible Factor (HIF)-1α has been shown to be essential for the inflammatory response of myeloid cells by regulating the metabolic switch to glycolysis, less is known about how HIF1α is triggered in inflammation. Here, we demonstrate that cells of the innate immune system require activity of the inositol-requiring enzyme 1α (IRE1α/XBP1) axis in order to initiate HIF1α-dependent production of cytokines such as IL1β, IL6 and VEGF-A. Knockout of either HIF1α or IRE1α in myeloid cells ameliorates vascular phenotypes in a model of retinal pathological angiogenesis driven by sterile inflammation. Thus, pathways associated with ER stress, in partnership with HIF1α, may co-regulate immune adaptation to low oxygen.
MeSH term(s)	Humans ; Protein Serine-Threonine Kinases/genetics ; Endoribonucleases ; Hypoxia ; Oxygen/metabolism ; Myeloid Cells/metabolism ; Inflammation/metabolism ; Hypoxia-Inducible Factor 1, alpha Subunit
Chemical Substances	Protein Serine-Threonine Kinases (EC 2.7.11.1) ; Endoribonucleases (EC 3.1.-) ; Oxygen (S88TT14065) ; Hypoxia-Inducible Factor 1, alpha Subunit
Language	English
Publishing date	2023-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-02793-y
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Article ; Online: Myeloid-resident neuropilin-1 promotes choroidal neovascularization while mitigating inflammation.

Andriessen, Elisabeth M M A / Binet, François / Fournier, Frédérik / Hata, Masayuki / Dejda, Agnieszka / Mawambo, Gaëlle / Crespo-Garcia, Sergio / Pilon, Frédérique / Buscarlet, Manuel / Beauchemin, Karine / Bougie, Véronique / Cumberlidge, Garth / Wilson, Ariel M / Bourgault, Steve / Rezende, Flavio A / Beaulieu, Normand / Delisle, Jean-Sébastien / Sapieha, Przemyslaw

EMBO molecular medicine

2021 Volume 13, Issue 5, Page(s) e11754

Abstract: Age-related macular degeneration (AMD) in its various forms is a leading cause of blindness in industrialized countries. Here, we provide evidence that ligands for neuropilin-1 (NRP1), such as Semaphorin 3A and VEGF-A, are elevated in the vitreous of ... ...

Abstract	Age-related macular degeneration (AMD) in its various forms is a leading cause of blindness in industrialized countries. Here, we provide evidence that ligands for neuropilin-1 (NRP1), such as Semaphorin 3A and VEGF-A, are elevated in the vitreous of patients with AMD at times of active choroidal neovascularization (CNV). We further demonstrate that NRP1-expressing myeloid cells promote and maintain CNV. Expression of NRP1 on cells of myeloid lineage is critical for mitigating production of inflammatory factors such as IL6 and IL1β. Therapeutically trapping ligands of NRP1 with an NRP1-derived trap reduces CNV. Collectively, our findings identify a role for NRP1-expressing myeloid cells in promoting pathological angiogenesis during CNV and introduce a therapeutic approach to counter neovascular AMD.
MeSH term(s)	Angiogenesis Inhibitors ; Choroidal Neovascularization ; Humans ; Inflammation ; Neuropilin-1/genetics ; Vascular Endothelial Growth Factor A ; Visual Acuity ; Wet Macular Degeneration
Chemical Substances	Angiogenesis Inhibitors ; Vascular Endothelial Growth Factor A ; Neuropilin-1 (144713-63-3)
Language	English
Publishing date	2021-04-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.201911754
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Article ; Online: miR-106b suppresses pathological retinal angiogenesis.

Ménard, Catherine / Wilson, Ariel M / Dejda, Agnieszka / Miloudi, Khalil / Binet, François / Crespo-Garcia, Sergio / Parinot, Célia / Pilon, Frédérique / Juneau, Rachel / Andriessen, Elisabeth Mma / Mawambo, Gaëlle / SanGiovanni, John Paul / De Guire, Vincent / Sapieha, Przemyslaw

Aging

2020 Volume 12, Issue 24, Page(s) 24836–24852

Abstract: MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. We recently demonstrated that levels of miR-106b were significantly decreased in the vitreous and plasma of patients with neovascular age-related macular ... ...

Abstract	MicroRNAs are small non-coding RNAs that post-transcriptionally regulate gene expression. We recently demonstrated that levels of miR-106b were significantly decreased in the vitreous and plasma of patients with neovascular age-related macular degeneration (AMD). Here we show that expression of the miR-106b-25 cluster is negatively regulated by the unfolded protein response pathway of protein kinase RNA-like ER kinase (PERK) in a mouse model of neovascular AMD. A reduction in levels of miR-106b triggers vascular growth both
MeSH term(s)	Animals ; Cell Line ; Cell Movement/genetics ; Choroidal Neovascularization/genetics ; Choroidal Neovascularization/pathology ; Diabetic Retinopathy ; Disease Models, Animal ; Endoplasmic Reticulum Stress/genetics ; Endothelial Cells ; Eye Burns ; Humans ; Laser Therapy ; Macular Degeneration/genetics ; Macular Degeneration/pathology ; Mice ; MicroRNAs/genetics ; Oxygen/toxicity ; Retinal Neovascularization/genetics ; Retinal Neovascularization/pathology ; Retinopathy of Prematurity ; Unfolded Protein Response/genetics ; eIF-2 Kinase/genetics ; eIF-2 Kinase/metabolism
Chemical Substances	MIRN106 microRNA, human ; MicroRNAs ; Mirn106 microRNA, mouse ; PERK kinase (EC 2.7.11.1) ; eIF-2 Kinase (EC 2.7.11.1) ; Oxygen (S88TT14065)
Language	English
Publishing date	2020-12-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.202404
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Article ; Online: Gut microbiota influences pathological angiogenesis in obesity-driven choroidal neovascularization.

Andriessen, Elisabeth Mma / Wilson, Ariel M / Mawambo, Gaelle / Dejda, Agnieszka / Miloudi, Khalil / Sennlaub, Florian / Sapieha, Przemyslaw

EMBO molecular medicine

2016 Volume 8, Issue 12, Page(s) 1366–1379

Abstract: Age-related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk ... ...

Abstract	Age-related macular degeneration in its neovascular form (NV AMD) is the leading cause of vision loss among adults above the age of 60. Epidemiological data suggest that in men, overall abdominal obesity is the second most important environmental risk factor after smoking for progression to late-stage NV AMD To date, the mechanisms that underscore this observation remain ill-defined. Given the impact of high-fat diets on gut microbiota, we investigated whether commensal microbes influence the evolution of AMD Using mouse models of NV AMD, microbiotal transplants, and other paradigms that modify the gut microbiome, we uncoupled weight gain from confounding factors and demonstrate that high-fat diets exacerbate choroidal neovascularization (CNV) by altering gut microbiota. Gut dysbiosis leads to heightened intestinal permeability and chronic low-grade inflammation characteristic of inflammaging with elevated production of IL-6, IL-1β, TNF-α, and VEGF-A that ultimately aggravate pathological angiogenesis.
MeSH term(s)	Animals ; Choroidal Neovascularization/pathology ; Cytokines/blood ; Diet, High-Fat/adverse effects ; Disease Models, Animal ; Dysbiosis/etiology ; Fecal Microbiota Transplantation ; Gastrointestinal Microbiome ; Gastrointestinal Tract/microbiology ; Inflammation/pathology ; Macular Degeneration/epidemiology ; Macular Degeneration/pathology ; Mice ; Neovascularization, Pathologic ; Obesity/complications ; Obesity/pathology
Chemical Substances	Cytokines
Language	English
Publishing date	2016-12-01
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2467145-9
ISSN	1757-4684 ; 1757-4676
ISSN (online)	1757-4684
ISSN	1757-4676
DOI	10.15252/emmm.201606531
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Article ; Online: Neuropilin-1 expression in adipose tissue macrophages protects against obesity and metabolic syndrome.

Wilson, Ariel Molly / Shao, Zhuo / Grenier, Vanessa / Mawambo, Gaëlle / Daudelin, Jean-François / Dejda, Agnieszka / Pilon, Frédérique / Popovic, Natalija / Boulet, Salix / Parinot, Célia / Oubaha, Malika / Labrecque, Nathalie / de Guire, Vincent / Laplante, Mathieu / Lettre, Guillaume / Sennlaub, Florian / Joyal, Jean-Sebastien / Meunier, Michel / Sapieha, Przemyslaw

Science immunology

2018 Volume 3, Issue 21

Abstract: Obesity gives rise to metabolic complications by mechanisms that are poorly understood. Although chronic inflammatory signaling in adipose tissue is typically associated with metabolic deficiencies linked to excessive weight gain, we identified a subset ... ...

Abstract	Obesity gives rise to metabolic complications by mechanisms that are poorly understood. Although chronic inflammatory signaling in adipose tissue is typically associated with metabolic deficiencies linked to excessive weight gain, we identified a subset of neuropilin-1 (NRP1)-expressing myeloid cells that accumulate in adipose tissue and protect against obesity and metabolic syndrome. Ablation of NRP1 in macrophages compromised lipid uptake in these cells, which reduced substrates for fatty acid β-oxidation and shifted energy metabolism of these macrophages toward a more inflammatory glycolytic metabolism. Conditional deletion of NRP1 in LysM Cre-expressing cells leads to inadequate adipose vascularization, accelerated weight gain, and reduced insulin sensitivity even independent of weight gain. Transfer of NRP1
MeSH term(s)	Adipose Tissue/metabolism ; Animals ; Macrophages/metabolism ; Metabolic Syndrome/metabolism ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuropilin-1/metabolism ; Obesity/metabolism
Chemical Substances	Neuropilin-1 (144713-63-3)
Language	English
Publishing date	2018-03-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.aan4626
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Article ; Online: Truncated netrin-1 contributes to pathological vascular permeability in diabetic retinopathy.

Miloudi, Khalil / Binet, François / Wilson, Ariel / Cerani, Agustin / Oubaha, Malika / Menard, Catherine / Henriques, Sullivan / Mawambo, Gaelle / Dejda, Agnieszka / Nguyen, Phuong Trang / Rezende, Flavio A / Bourgault, Steve / Kennedy, Timothy E / Sapieha, Przemyslaw

The Journal of clinical investigation

2016 Volume 126, Issue 8, Page(s) 3006–3022

Abstract: Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is closely associated with the deterioration of central ... ...

Abstract	Diabetic retinopathy (DR) is a major complication of diabetes and a leading cause of blindness in the working-age population. Impaired blood-retinal barrier function leads to macular edema that is closely associated with the deterioration of central vision. We previously demonstrated that the neuronal guidance cue netrin-1 activates a program of reparative angiogenesis in microglia within the ischemic retina. Here, we provide evidence in both vitreous humor of diabetic patients and in retina of a murine model of diabetes that netrin-1 is metabolized into a bioactive fragment corresponding to domains VI and V of the full-length molecule. In contrast to the protective effects of full-length netrin-1 on retinal microvasculature, the VI-V fragment promoted vascular permeability through the uncoordinated 5B (UNC5B) receptor. The collagenase matrix metalloprotease 9 (MMP-9), which is increased in patients with diabetic macular edema, was capable of cleaving netrin-1 into the VI-V fragment. Thus, MMP-9 may release netrin-1 fragments from the extracellular matrix and facilitate diffusion. Nonspecific inhibition of collagenases or selective inhibition of MMP-9 decreased pathological vascular permeability in a murine model of diabetic retinal edema. This study reveals that netrin-1 degradation products are capable of modulating vascular permeability, suggesting that these fragments are of potential therapeutic interest for the treatment of DR.
MeSH term(s)	Aged ; Aged, 80 and over ; Animals ; Blood-Retinal Barrier ; Capillary Permeability ; Case-Control Studies ; Diabetes Mellitus, Experimental ; Diabetic Retinopathy/genetics ; Diabetic Retinopathy/metabolism ; Disease Models, Animal ; Humans ; Macular Edema/metabolism ; Matrix Metalloproteinase 9/metabolism ; Mice ; Mice, Inbred C57BL ; Microglia/metabolism ; Middle Aged ; Nerve Growth Factors/genetics ; Nerve Growth Factors/metabolism ; Netrin-1 ; Protein Domains ; Retina/metabolism ; Streptozocin ; Tumor Suppressor Proteins/genetics ; Tumor Suppressor Proteins/metabolism
Chemical Substances	NTN1 protein, human ; Nerve Growth Factors ; Ntn1 protein, mouse ; Tumor Suppressor Proteins ; Netrin-1 (158651-98-0) ; Streptozocin (5W494URQ81) ; MMP9 protein, human (EC 3.4.24.35) ; Matrix Metalloproteinase 9 (EC 3.4.24.35)
Language	English
Publishing date	2016--01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3067-3
ISSN	1558-8238 ; 0021-9738
ISSN (online)	1558-8238
ISSN	0021-9738
DOI	10.1172/JCI84767
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Article ; Online: Senescence-associated secretory phenotype contributes to pathological angiogenesis in retinopathy.

Oubaha, Malika / Miloudi, Khalil / Dejda, Agnieszka / Guber, Vera / Mawambo, Gaëlle / Germain, Marie-Anne / Bourdel, Guillaume / Popovic, Natalija / Rezende, Flavio A / Kaufman, Randal J / Mallette, Frédérick A / Sapieha, Przemyslaw

Science translational medicine

2016 Volume 8, Issue 362, Page(s) 362ra144

Abstract: Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a ... ...

Abstract	Pathological angiogenesis is the hallmark of diseases such as cancer and retinopathies. Although tissue hypoxia and inflammation are recognized as central drivers of vessel growth, relatively little is known about the process that bridges the two. In a mouse model of ischemic retinopathy, we found that hypoxic regions of the retina showed only modest rates of apoptosis despite severely compromised metabolic supply. Using transcriptomic analysis and inducible loss-of-function genetics, we demonstrated that ischemic retinal cells instead engage the endoplasmic reticulum stress inositol-requiring enzyme 1α (IRE1α) pathway that, through its endoribonuclease activity, induces a state of senescence in which cells adopt a senescence-associated secretory phenotype (SASP). We also detected SASP-associated cytokines (plasminogen activator inhibitor 1, interleukin-6, interleukin-8, and vascular endothelial growth factor) in the vitreous humor of patients suffering from proliferative diabetic retinopathy. Therapeutic inhibition of the SASP through intravitreal delivery of metformin or interference with effectors of senescence (semaphorin 3A or IRE1α) in mice reduced destructive retinal neovascularization in vivo. We conclude that the SASP contributes to pathological vessel growth, with ischemic retinal cells becoming prematurely senescent and secreting inflammatory cytokines that drive paracrine senescence, exacerbate destructive angiogenesis, and hinder reparative vascular regeneration. Reversal of this process may be therapeutically beneficial.
Language	English
Publishing date	2016-10-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aaf9440
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Article ; Online: Neuropilin-1-Expressing Microglia Are Associated With Nascent Retinal Vasculature Yet Dispensable for Developmental Angiogenesis.

Dejda, Agnieszka / Mawambo, Gaelle / Daudelin, Jean-Francois / Miloudi, Khalil / Akla, Naoufal / Patel, Chintan / Andriessen, Elisabeth M M A / Labrecque, Nathalie / Sennlaub, Florian / Sapieha, Przemyslaw

Investigative ophthalmology & visual science

2016 Volume 57, Issue 4, Page(s) 1530–1536

Abstract: Purpose: Neuropilin-1 (NRP-1) is a transmembrane receptor that is critical for vascular development within the central nervous system (CNS). It binds and influences signaling of several key angiogenic factors, such as VEGF-165, semaphorin 3A, platelet ... ...

Abstract	Purpose: Neuropilin-1 (NRP-1) is a transmembrane receptor that is critical for vascular development within the central nervous system (CNS). It binds and influences signaling of several key angiogenic factors, such as VEGF-165, semaphorin 3A, platelet derived growth factor, and more. Neuropilin-1 is expressed by neurons and endothelial cells as well as a subpopulation of proangiogenic macrophages/microglia that are thought to interact with endothelial tip cells to promote vascular anastomosis during brain vascularization. We previously demonstrated a significant role for NRP-1 in macrophage chemotaxis and showed that NRP-1-expressing microglia are major contributors to pathologic retinal angiogenesis. Given this influence on CNS angiogenesis, we now investigated the involvement of microglia-resident NRP-1 in developmental retinal vascularization. Methods: We followed NRP-1 expressing microglia during retinal development. We used LysM-cre myeloid lineage-driver cre mice to reduce expression of NRP-1 in retinal myeloid-derived cells and performed a comprehensive morphometric analysis of retinal vasculature during development. Results: We provide evidence that NRP-1+ microglia are present throughout the retina during vascular development with a preference for the non-vascularized retina. Using LysM-Cre/Nrp1(fl/fl) mice, we reduced NRP-1 expression by ~65% in retinal microglia and demonstrate that deficiency in NRP-1 in these microglia does not impair retinal angiogenesis. Conclusions: Our data draw a dichotomous role for NRP-1 in cells of myeloid lineage where it is dispensable for adequate retinal developmental vascularization yet obligate for pathologic retinal angiogenesis.
MeSH term(s)	Animals ; Animals, Newborn ; Bacterial Proteins/metabolism ; Endothelium, Vascular ; Female ; Flow Cytometry ; Fluorescent Antibody Technique, Indirect ; Fluorescent Dyes/metabolism ; Luminescent Proteins/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microglia/physiology ; Morphogenesis/physiology ; Myeloid Cells/metabolism ; Neovascularization, Physiologic/physiology ; Neuropilin-1/metabolism ; Retinal Vessels/physiology ; Signal Transduction
Chemical Substances	Bacterial Proteins ; Fluorescent Dyes ; Luminescent Proteins ; yellow fluorescent protein, Bacteria ; Neuropilin-1 (144713-63-3)
Language	English
Publishing date	2016-04
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	391794-0
ISSN	1552-5783 ; 0146-0404
ISSN (online)	1552-5783
ISSN	0146-0404
DOI	10.1167/iovs.15-18598
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Article ; Online: NOTCH1 signaling induces pathological vascular permeability in diabetic retinopathy.

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 10, Page(s) 4538–4547

Abstract: Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature ... ...

Abstract	Diabetic macular edema is a major complication of diabetes resulting in loss of central vision. Although heightened vessel leakiness has been linked to glial and neuronal-derived factors, relatively little is known on the mechanisms by which mature endothelial cells exit from a quiescent state and compromise barrier function. Here we report that endothelial NOTCH1 signaling in mature diabetic retinas contributes to increased vascular permeability. By providing both human and mouse data, we show that NOTCH1 ligands JAGGED1 and DELTA LIKE-4 are up-regulated secondary to hyperglycemia and activate both canonical and rapid noncanonical NOTCH1 pathways that ultimately disrupt endothelial adherens junctions in diabetic retinas by causing dissociation of vascular endothelial-cadherin from β-catenin. We further demonstrate that neutralization of NOTCH1 ligands prevents diabetes-induced retinal edema. Collectively, these results identify a fundamental process in diabetes-mediated vascular permeability and provide translational rational for targeting the NOTCH pathway (primarily JAGGED1) in conditions characterized by compromised vascular barrier function.
MeSH term(s)	Adaptor Proteins, Signal Transducing/biosynthesis ; Animals ; Antigens, CD/metabolism ; Cadherins/metabolism ; Calcium-Binding Proteins/biosynthesis ; Capillary Permeability ; Diabetic Retinopathy/pathology ; Enzyme Activation ; Hyperglycemia/metabolism ; Jagged-1 Protein/biosynthesis ; Mice ; Nitric Oxide/biosynthesis ; Receptor, Notch1/metabolism ; Retinal Vessels/metabolism ; Signal Transduction ; Vascular Endothelial Growth Factor Receptor-2/metabolism ; src-Family Kinases/metabolism
Chemical Substances	Adaptor Proteins, Signal Transducing ; Antigens, CD ; Cadherins ; Calcium-Binding Proteins ; DLL4 protein, mouse ; Jag1 protein, mouse ; Jagged-1 Protein ; Notch1 protein, mouse ; Receptor, Notch1 ; cadherin 5 ; Nitric Oxide (31C4KY9ESH) ; Vascular Endothelial Growth Factor Receptor-2 (EC 2.7.10.1) ; src-Family Kinases (EC 2.7.10.2)
Language	English
Publishing date	2019-02-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1814711116
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Article ; Online: Neutrophil extracellular traps target senescent vasculature for tissue remodeling in retinopathy.

Binet, François / Cagnone, Gael / Crespo-Garcia, Sergio / Hata, Masayuki / Neault, Mathieu / Dejda, Agnieszka / Wilson, Ariel M / Buscarlet, Manuel / Mawambo, Gaelle Tagne / Howard, Joel P / Diaz-Marin, Roberto / Parinot, Celia / Guber, Vera / Pilon, Frédérique / Juneau, Rachel / Laflamme, Rémi / Sawchyn, Christina / Boulay, Karine / Leclerc, Severine /

Abu-Thuraia, Afnan / Côté, Jean-François / Andelfinger, Gregor / Rezende, Flavio A / Sennlaub, Florian / Joyal, Jean-Sébastien / Mallette, Frédérick A / Sapieha, Przemyslaw

Science (New York, N.Y.)

2020 Volume 369, Issue 6506

Abstract: In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening ... ...

Abstract	In developed countries, the leading causes of blindness such as diabetic retinopathy are characterized by disorganized vasculature that can become fibrotic. Although many such pathological vessels often naturally regress and spare sight-threatening complications, the underlying mechanisms remain unknown. Here, we used orthogonal approaches in human patients with proliferative diabetic retinopathy and a mouse model of ischemic retinopathies to identify an unconventional role for neutrophils in vascular remodeling during late-stage sterile inflammation. Senescent vasculature released a secretome that attracted neutrophils and triggered the production of neutrophil extracellular traps (NETs). NETs ultimately cleared diseased endothelial cells and remodeled unhealthy vessels. Genetic or pharmacological inhibition of NETosis prevented the regression of senescent vessels and prolonged disease. Thus, clearance of senescent retinal blood vessels leads to reparative vascular remodeling.
MeSH term(s)	Aging/pathology ; Animals ; Cellular Senescence ; Diabetic Retinopathy/immunology ; Diabetic Retinopathy/pathology ; Disease Models, Animal ; Endothelial Cells/immunology ; Endothelial Cells/pathology ; Extracellular Traps/immunology ; Humans ; Inflammation/immunology ; Inflammation/pathology ; Mice ; Mice, Inbred C57BL ; Neutrophils/immunology ; Retinal Vessels/immunology ; Retinal Vessels/pathology
Language	English
Publishing date	2020-08-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.aay5356
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