Microglia/Macrophages Migrate through Retinal Epithelium Barrier by a Transcellular Route in Diabetic Retinopathy Role of PKC zeta in the Goto Kakizaki Rat Model

作者：Omri Samy; Behar Cohen Francine; de Kozak Yvonne; Sennlaub Florian; Verissimo Lourena Mafra; Jonet Laurent; Savoldelli Michele; Omri Boubaker; Crisanti Patricia^*

来源：American Journal Of Pathology, 2011, 179(2): 942-953.

DOI：10.1016/j.ajpath.2011.04.018

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 C zeta (PKC zeta) 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 PKC zeta 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 PKC zeta 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. (Am J Pathol 2011, 179:942-953; DOI: 10.1016/j.ajpath.2011.04.018)

• 出版日期2011-8