A damaging attraction
Vasoproliferative retinopathies, such as proliferative diabetic retinopathy (PDR), are a major cause of blindness in industrialized nations. In PDR, degeneration of microvasculature in the retina results in neuroretinal ischemic stress, which then induces aberrant angiogenesis. Mononuclear phagocytes (MPs) are elevated in these diseases; however, the signals and mechanisms that mediate recruitment of innate immune cells to the retina are poorly understood. Using a murine oxygen-induced retinopathy (OIR) model of PDR, Agnieszka Dejda, Gaelle Mawambo, and colleagues at the University of Montreal determined that MPs expressing neuropilin-1 (NRP-1) localize to sites of neovascularization in the retina following OIR. The authors found that the NRP-1 ligand semaphorin 3A (SEMA3A) is elevated in patients with late-stage PDR, and in mice, both SEMA3A and NRP-1 ligand VEGF are induced in the retinal ganglion cell layer during OIR and recruit circulating NRP-1-expressing MPs. Compared to WT animals, mice with NRP-1-deficient MPs exhibited less vascular degeneration and pathological neovascularization during OIR. Moreover, intravitrial administration of soluble NRP-1 reduced MP infiltration and pathological neovascularization in OIR-induced retinopathy. The results of this study identify proangiogenic NRP-1-expressing MPs as mediators of destructive ocular inflammation and suggest that targeting NRP-1 has potential to limit neural ischemia-induced damage. The accompanying image shows a corrosion cast of normal mouse retinal vasculature imaged by environmental scanning electron microscopy (ESEM). In diabetic retinopathy, the vascular beds seen here degenerate and later proliferate and grow in a disorganized fashion.
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Abstract
Immunological activity in the CNS is largely dependent on an innate immune response and is heightened in diseases, such as diabetic retinopathy, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s disease. The molecular dynamics governing immune cell recruitment to sites of injury and disease in the CNS during sterile inflammation remain poorly defined. Here, we identified a subset of mononuclear phagocytes (MPs) that responds to local chemotactic cues that are conserved among central neurons, vessels, and immune cells. Patients suffering from late-stage proliferative diabetic retinopathy (PDR) had elevated vitreous semaphorin 3A (SEMA3A). Using a murine model, we found that SEMA3A acts as a potent attractant for neuropilin-1–positive (NRP-1–positive) MPs. These proangiogenic MPs were selectively recruited to sites of pathological neovascularization in response to locally produced SEMA3A as well as VEGF. NRP-1–positive MPs were essential for disease progression, as NRP-1–deficient MPs failed to enter the retina in a murine model of oxygen-induced retinopathy (OIR), a proxy for PDR. OIR mice with NRP-1–deficient MPs exhibited decreased vascular degeneration and diminished pathological preretinal neovascularization. Intravitreal administration of a NRP-1–derived trap effectively mimicked the therapeutic benefits observed in mice lacking NRP-1–expressing MPs. Our findings indicate that NRP-1 is an obligate receptor for MP chemotaxis, bridging neural ischemia to an innate immune response in neovascular retinal disease.
Authors
Agnieszka Dejda, Gaelle Mawambo, Agustin Cerani, Khalil Miloudi, Zhuo Shao, Jean-Francois Daudelin, Salix Boulet, Malika Oubaha, Felix Beaudoin, Naoufal Akla, Sullivan Henriques, Catherine Menard, Andreas Stahl, Jean-Sébastien Delisle, Flavio A. Rezende, Nathalie Labrecque, Przemyslaw Sapieha
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ISSN: 0021-9738 (print), 1558-8238 (online)