p75NTR and Its Ligand ProNGF Activate Paracrine Mechanisms Etiological to the Vascular, Inflammatory, and Neurodegenerative Pathologies of Diabetic Retinopathy.

Abstract

UNLABELLED:

In many diseases, expression and ligand-dependent activity of the p75(NTR) receptor can promote pericyte and vascular dysfunction, inflammation, glial activation, and neurodegeneration. Diabetic retinopathy (DR) is characterized by all of these pathological events. However, the mechanisms by which p75(NTR) may be implicated at each stage of DR pathology remain poorly understood. Using a streptozotocin mouse model of diabetic retinopathy, we report that p75(NTR) is upregulated very early in glia and in pericytes to mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood-retina barrier breakdown, edema, and neuronal death. In a mouse model of oxygen-induced retinopathy, mimicking proliferative DR, p75(NTR)-dependent inflammation leads to ischemia and pathological angiogenesis through Semaphorin 3A. The acute use of antagonists of p75(NTR) or antagonists of the ligand proNGF suppresses each distinct phase of pathology, ameliorate disease, and prevent disease progression. Thus, our study documents novel disease mechanisms and validates druggable targets for diabetic retinopathy.

SIGNIFICANCE STATEMENT:

Diabetic retinopathy (DR) affects an estimated 250 million people and has no effective treatment. Stages of progression comprise pericyte/vascular dysfunction, inflammation, glial activation, and neurodegeneration. The pathophysiology of each stage remains unclear. We postulated that the activity of p75NTR may be implicated. We show that p75NTR in glia and in pericytes mediate ligand-dependent induction of inflammatory cytokines, disruption of the neuro-glia-vascular unit, promotion of blood-retina barrier breakdown, edema, and neuronal death. p75NTR-promoted inflammation leads to ischemia and angiogenesis through Semaphorin 3A. Antagonists of p75NTR or antagonists of proNGF suppress each distinct phase of pathology, ameliorate disease, and prevent disease progression. Our study documents novel mechanisms in a pervasive disease and validates druggable targets for treatment.

• Authors: Pablo F Barcelona, Nicholas Sitaras, Alba Galan, Gema Esquiva, Sean Jmaeff, Yifan Jian, Marinko V Sarunic, Nicolas Cuenca, Przemyslaw Sapieha, H Uri Saragovi
• Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci) Vol. 36 Issue 34 Pg. 8826-41 (08 24 2016) ISSN: 1529-2401 [Electronic] United States
• PMID: 27559166 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 the authors 0270-6474/16/368826-16$15.00/0.

Chemical References

• Antibodies
• Culture Media, Conditioned
• Cytokines
• Protein Precursors
• Receptors, Nerve Growth Factor
• Ngfr protein, mouse
• pro-nerve growth factor, mouse
• Streptozocin
• Nerve Growth Factor

Topics

• Animals
• Animals, Newborn
• Antibodies (pharmacology)
• Astrocytes (chemistry)
• Cells, Cultured
• Culture Media, Conditioned (pharmacology)
• Cytokines (genetics, metabolism)
• Diabetic Retinopathy (chemically induced, complications)
• Disease Models, Animal
• Endothelial Cells (drug effects, physiology)
• Female
• Gene Expression Regulation, Developmental (drug effects, physiology)
• In Situ Nick-End Labeling
• Inflammation (etiology)
• Male
• Mice
• Mice, Inbred C57BL
• Nerve Growth Factor (immunology, metabolism)
• Neurodegenerative Diseases (etiology)
• Protein Precursors (immunology, metabolism)
• Rats
• Receptors, Nerve Growth Factor (immunology, metabolism)
• Retina (pathology)
• Streptozocin (toxicity)
• Tomography, Optical Coherence
• Vascular Diseases (etiology)
• Visual Pathways (pathology)