title: Microglia/macrophages migrate through retinal epithelium barrier by a transcellular route in diabetic retinopathy: role of PKCζ in the Goto Kakizaki rat model.
abstract: Diabetic retinopathy is associated with ocular inflammation, leading to retinal barrier breakdown, macular edema, and visual cell loss. We investigated the molecular mechanisms involved in microglia/macrophages trafficking in the retina and the role of protein kinase Cζ (PKCζ) in this process. Goto Kakizaki (GK) rats, a model for spontaneous type 2 diabetes were studied until 12 months of hyperglycemia. Up to 5 months, sparse microglia/macrophages were detected in the subretinal space, together with numerous pores in retinal pigment epithelial (RPE) cells, allowing inflammatory cell traffic between the retina and choroid. Intercellular adhesion molecule-1 (ICAM-1), caveolin-1 (CAV-1), and PKCζ were identified at the pore border. At 12 months of hyperglycemia, the significant reduction of pores density in RPE cell layer was associated with microglia/macrophages accumulation in the subretinal space together with vacuolization of RPE cells and disorganization of photoreceptors outer segments. The intraocular injection of a PKCζ inhibitor at 12 months reduced iNOS expression in microglia/macrophages and inhibited their migration through the retina, preventing their subretinal accumulation. We show here that a physiological transcellular pathway takes place through RPE cells and contributes to microglia/macrophages retinal trafficking. Chronic hyperglycemia causes alteration of this pathway and subsequent subretinal accumulation of activated microglia/macrophages.
authors.affiliation: INSERM, U872 Physiopathology of Ocular Diseases, Therapeutic Innovations, Paris, France.
authors.forename: Samy
authors.initials: S
authors.lastname: Omri
authors.forename: Francine
authors.initials: F
authors.lastname: Behar-Cohen
authors.forename: Yvonne
authors.initials: Y
authors.lastname: de Kozak
authors.forename: Florian
authors.initials: F
authors.lastname: Sennlaub
authors.forename: Lourena Mafra
authors.initials: LM
authors.lastname: Verissimo
authors.forename: Laurent
authors.initials: L
authors.lastname: Jonet
authors.forename: Michèle
authors.initials: M
authors.lastname: Savoldelli
authors.forename: Boubaker
authors.initials: B
authors.lastname: Omri
authors.forename: Patricia
authors.initials: P
authors.lastname: Crisanti
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002465:Cell Movement; D003930:Diabetic Retinopathy / Q000378:metabolism*; D004847:Epithelial Cells / Q000378:metabolism*; D007249:Inflammation; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D008264:Macrophages / Q000378:metabolism*; D017628:Microglia / Q000378:metabolism*; D018613:Microscopy, Confocal / Q000379:methods; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D012160:Retina / Q000378:metabolism*; D000099221:Protein Kinase C zeta
chemical_list: D001786:Blood Glucose; D018799:Intercellular Adhesion Molecule-1; D011493:Protein Kinase C; D000099221:Protein Kinase C zeta