The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration
<p>The mouse retina is a model system to analyzing angiogenesis. The mouse retina is a robust tool to analyze in vivo angiogenesis. The avascular retinal vasculature develops gradually as vessels start to grow into the tissue. Starting at postnatal day 0 (P0), blood vessels branch out in a single plane until approximately P8, which allows monitoring of the vessel growth in an intact system including endothelial cells, pericytes, neurons, microglia, astrocytes and Müller cells. Genotype-specific alteration can be analyzed, which may provide insight into molecular and cellular mechanisms of the regulation of angiogenesis. (<b>A</b>) Overview of the retina vasculature stained with the endothelial cell marker platelet endothelial cell adhesion molecule (PECAM; CD31) at P5. The retinal leaves show the branching of the multiple retinal vasculatures. The vessels were stained with (<b>B</b>) PECAM and <b>C</b> ERG to mark endothelial cells and their nuclei, respectively. Scale bar in (<b>A</b>) 500 µm, in (<b>B</b>,<b>C</b>) 250 µm.</p> "> Figure 2
<p>Possible mechanisms underlying microglial activation and subsequent inflammatory responses in diabetic retinopathy. Ramified microglia are influenced by hyperglycemia, alterations in ischemia, vessel leakage and upregulation of various mediators. Microglia activation means morphological changes, proliferation and migration. This activation results in an inflammatory response, including downregulation (down arrow) of cytokine IL-10 and growth factors as well as upregulation (up arrow) of various cytokines, chemokines and neurotoxins.</p> ">
Abstract
:1. Introduction
2. The Retina
3. Diabetic Retinopathy
3.1. Hyperglycemia in Diabetic Retinopathy
3.2. Leukostasis in Diabetic Retinopathy
4. Microglia
4.1. Microglia in the Retina
4.2. Inflammation in Diabetic Retinopathy
4.3. Microglia Activation in Diabetic Retinopathy
5. Molecular Pathways of Inflammation in Diabetic Retinopathy
5.1. Cytokines
5.2. VEGF
5.3. TNFα
5.4. Chemokines
5.5. Novel Molecular Targets in Diabetic Retinopathy
6. Neurodegeneration in Diabetic Retinopathy
7. The Influence of Microglia on Neurodegeneration in Diabetic Retinopathy
8. Microvascular Pathology and Defective BRB Integrity
9. Angiogenesis and Inflammation
10. Interaction of Microglia with Macroglia in the Retina
11. Treatment of Diabetic Retinopathy by Altering Microglia
11.1. Photocoagulation
11.2. VEGF Blocking
11.3. Steroid Therapy
11.4. Direct Prevention of Microglia Activation
12. Conclusions and Perspectives
Acknowledgments
Author Contributions
Conflicts of Interest
Abbreviations
AMPA | α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate |
C5aR | anaphylatoxin C5a receptor |
BRB | blood-retina barrier |
CCL | CC chemokine ligands |
CNS | central nervous system |
CX3CL | chemokine (C-X3-C motif) ligand |
COX | cyclooxygenase |
DME | diabetic macular edema |
DR | diabetic retinopathy |
ERG | electroretinogram |
ERK | extracellular signal–regulated kinase |
HIF | hypoxia-inducible factor |
IL | interleukins |
ICAM | intracellular adhesion molecule |
IRBP | iron-responsive element-binding proteins |
MMP | matrix metalloproteases |
MCP | membrane cofactor protein |
NMDA | N-methyl-d-aspartame |
NOX | nicotinamide adenine dinucleotide phosphate (NADPH) oxidases |
NGF | nerve growth factor |
NO | nitric oxide |
AGE | advanced glycation end products |
LEP | leptin |
NPDR | non-proliferating diabetic retinopathy |
NF | nuclear factor |
PEDF | pigment epithelium-derived factor |
PDR | proliferating diabetic retinopathy |
ROS | reactive oxygen species |
RBP | retinol-binding protein |
STAT | signal transducer and activator of transcription |
TNF | tumor necrosis factor |
VCAM | vascular cell adhesion molecule |
VEGF | vascular endothelial growth factor |
ZO | zonula occludens |
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Mediators | Regulation | Relevance | References |
---|---|---|---|
Cytokines | |||
IL-1β | ↑ | Immuno-stimulation Increased ICAM-1 | [28,168,169,170,171] |
IL-6 | ↑ | Immuno-stimulation | [172,173] |
IL-8 | ↑ | Immuno-stimulation | [173] |
IL-18 | ↑ | Immuno-stimulation | [174,175,176] |
VEGF | ↑ | Immuno-stimulation Angio-stimulation Neuroprotective | [177] |
TNFα | ↑ | Immuno-stimulation Increased ICAM-1 Increased leukostasis | [28,168,178,179,180] |
COX-2 | ↑ | Immuno-stimulation | [180] |
Chemokines | |||
CCL-2 | ↑ | Immuno-stimulation | [181] |
CCL-4 | ↑ | Immuno-stimulation | [181] |
CXCL-9 | ↑ | Immuno-stimulation | [181] |
CXCL-10 | ↑ | Immuno-stimulation | [181] |
MCP-1 | ↑ | Immuno-stimulation Increased fibrosis Angio-stimulation | [28,173,182] |
CX3CL1 | ↑ | Immuno-stimulation Neuroprotective | [183] |
Growth factors | |||
NGF | ↓ | Cellular toxicity | [184] |
PEDF | ↓ | Cellular toxicity | [184] |
IRBP | ↓ | Cellular toxicity | [184] |
Somatostatin | ↓ | Cellular toxicity | [184] |
Adhesion molecules | |||
ICAM-1 | ↑ | Increased leukostasis | [64,65,66] |
VCAM-1 | ↑ | Increased leukostasis | [64,65,66] |
Neurotoxins | |||
ROS | ↑ | Cellular toxicity | [185] |
NO | ↑ | Cellular toxicity | [185] |
Glutamate | ↑ | Cellular toxicity | [185] |
Caspase-3 | ↑ | Cellular toxicity | [185] |
Others | |||
LPS | ↑ | Immuno-stimulation Cellular toxicity | [106] |
AGE | ↑ | Immuno-stimulation Cellular toxicity | [49,50,51,52,53,54,55,56] |
LEP | ↑ | Immuno-stimulation Cellular toxicity | [49,50,51,52,53,54,55,56] |
Angiopoietin-2 | ↑ | Angio-stimulation | [186,187] |
RBP4 | ↑ | Immuno-stimulation Neurotoxic Increased vascular leakage | [174,175,176] |
NOX-1/4 | ↑ | Immuno-stimulation Increased leukostasis Increased ROS Increased vascular leakage | [188] |
MMP-2/9 | ↑ | Immuno-stimulation Increased chemokines Neurotoxic | [189,190,191,192,193,194] |
STAT3 | ↑ | Immuno-stimulation Increased vascular leakage | [195,196] |
Wnt | ↑ | Immuno-stimulation Increased ROS | [197] |
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Altmann, C.; Schmidt, M.H.H. The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. Int. J. Mol. Sci. 2018, 19, 110. https://doi.org/10.3390/ijms19010110
Altmann C, Schmidt MHH. The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration. International Journal of Molecular Sciences. 2018; 19(1):110. https://doi.org/10.3390/ijms19010110
Chicago/Turabian StyleAltmann, Christine, and Mirko H. H. Schmidt. 2018. "The Role of Microglia in Diabetic Retinopathy: Inflammation, Microvasculature Defects and Neurodegeneration" International Journal of Molecular Sciences 19, no. 1: 110. https://doi.org/10.3390/ijms19010110