title: Neuropilin-1 mediates myeloid cell chemoattraction and influences retinal neuroimmune crosstalk.
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.forename: Agnieszka
authors.initials: A
authors.lastname: Dejda
authors.forename: Gaelle
authors.initials: G
authors.lastname: Mawambo
authors.forename: Agustin
authors.initials: A
authors.lastname: Cerani
authors.forename: Khalil
authors.initials: K
authors.lastname: Miloudi
authors.forename: Zhuo
authors.initials: Z
authors.lastname: Shao
authors.forename: Jean-Francois
authors.initials: JF
authors.lastname: Daudelin
authors.forename: Salix
authors.initials: S
authors.lastname: Boulet
authors.forename: Malika
authors.initials: M
authors.lastname: Oubaha
authors.forename: Felix
authors.initials: F
authors.lastname: Beaudoin
authors.forename: Naoufal
authors.initials: N
authors.lastname: Akla
authors.forename: Sullivan
authors.initials: S
authors.lastname: Henriques
authors.forename: Catherine
authors.initials: C
authors.lastname: Menard
authors.forename: Andreas
authors.initials: A
authors.lastname: Stahl
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Delisle
authors.forename: Flavio A
authors.initials: FA
authors.lastname: Rezende
authors.forename: Nathalie
authors.initials: N
authors.lastname: Labrecque
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Sapieha
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D002633:Chemotaxis; D002829:Choroid / Q000276:immunology; D003930:Diabetic Retinopathy / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D012157:Mononuclear Phagocyte System / Q000276:immunology; D022423:Myeloid Cells / Q000502:physiology*; D018919:Neovascularization, Physiologic; D015213:Neuroimmunomodulation; D039942:Neuropilin-1 / Q000502:physiology*; D040121:Semaphorin-3A / Q000378:metabolism; D046509:Tissue Culture Techniques
chemical_list: C108639:SEMA3A protein, human; D040121:Semaphorin-3A; D039942:Neuropilin-1