Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses

Abdelrahman Y. Fouda, Zhimin Xu, Esraa Shosha, Tahira Lemtalsi, Jijun Chen, Haroldo A. Toque, Rebekah Tritz, Xuezhi Cui, Brian K. Stansfield, Yuqing Huo, Paulo C. Rodriguez, Sylvia B. Smith, R. William Caldwell, S. Priya Narayanan, Ruth B. Caldwell

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/ knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

Original languageEnglish (US)
Article number1001
JournalCell Death and Disease
Volume9
Issue number10
DOIs
StatePublished - Oct 1 2018

Fingerprint

Arginase
Ischemia
Macrophages
Reperfusion Injury
Knockout Mice
Ureohydrolases
Nitric Oxide Synthase
Arginine
Wounds and Injuries
Clodronic Acid
Retinal Degeneration
Intravitreal Injections
Nitric Oxide Synthase Type III
Vascular System Injuries
Nitric Oxide Synthase Type II

ASJC Scopus subject areas

  • Immunology
  • Cellular and Molecular Neuroscience
  • Cell Biology
  • Cancer Research

Cite this

Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. / Fouda, Abdelrahman Y.; Xu, Zhimin; Shosha, Esraa; Lemtalsi, Tahira; Chen, Jijun; Toque, Haroldo A.; Tritz, Rebekah; Cui, Xuezhi; Stansfield, Brian K.; Huo, Yuqing; Rodriguez, Paulo C.; Smith, Sylvia B.; Caldwell, R. William; Narayanan, S. Priya; Caldwell, Ruth B.

In: Cell Death and Disease, Vol. 9, No. 10, 1001, 01.10.2018.

Research output: Contribution to journalArticle

Fouda, Abdelrahman Y. ; Xu, Zhimin ; Shosha, Esraa ; Lemtalsi, Tahira ; Chen, Jijun ; Toque, Haroldo A. ; Tritz, Rebekah ; Cui, Xuezhi ; Stansfield, Brian K. ; Huo, Yuqing ; Rodriguez, Paulo C. ; Smith, Sylvia B. ; Caldwell, R. William ; Narayanan, S. Priya ; Caldwell, Ruth B. / Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses. In: Cell Death and Disease. 2018 ; Vol. 9, No. 10.
@article{acf5198a06f84cfb8c9ff51b6fbd263b,
title = "Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses",
abstract = "The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/ − knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.",
author = "Fouda, {Abdelrahman Y.} and Zhimin Xu and Esraa Shosha and Tahira Lemtalsi and Jijun Chen and Toque, {Haroldo A.} and Rebekah Tritz and Xuezhi Cui and Stansfield, {Brian K.} and Yuqing Huo and Rodriguez, {Paulo C.} and Smith, {Sylvia B.} and Caldwell, {R. William} and Narayanan, {S. Priya} and Caldwell, {Ruth B.}",
year = "2018",
month = "10",
day = "1",
doi = "10.1038/s41419-018-1051-6",
language = "English (US)",
volume = "9",
journal = "Cell Death and Disease",
issn = "2041-4889",
publisher = "Nature Publishing Group",
number = "10",

}

TY - JOUR

T1 - Arginase 1 promotes retinal neurovascular protection from ischemia through suppression of macrophage inflammatory responses

AU - Fouda, Abdelrahman Y.

AU - Xu, Zhimin

AU - Shosha, Esraa

AU - Lemtalsi, Tahira

AU - Chen, Jijun

AU - Toque, Haroldo A.

AU - Tritz, Rebekah

AU - Cui, Xuezhi

AU - Stansfield, Brian K.

AU - Huo, Yuqing

AU - Rodriguez, Paulo C.

AU - Smith, Sylvia B.

AU - Caldwell, R. William

AU - Narayanan, S. Priya

AU - Caldwell, Ruth B.

PY - 2018/10/1

Y1 - 2018/10/1

N2 - The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/ − knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

AB - The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/ − knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

UR - http://www.scopus.com/inward/record.url?scp=85053819091&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85053819091&partnerID=8YFLogxK

U2 - 10.1038/s41419-018-1051-6

DO - 10.1038/s41419-018-1051-6

M3 - Article

C2 - 30254218

AN - SCOPUS:85053819091

VL - 9

JO - Cell Death and Disease

JF - Cell Death and Disease

SN - 2041-4889

IS - 10

M1 - 1001

ER -