High-glucose stimulation triggers early transcription of a panel of proinflammatory mediators in rat Muller glia cells and retina primary explants.

Several preclinical data support a main role of Muller glia, a type of retinal glial cells, in sensing hyperglycemia and, subsequently, acquiring a pro-inflammatory polarization during diabetic retinopathy onset and progression. Recently, we reported that stimulation of rat Muller glia cells (rMC1) with high glucose triggers a very early (< 15 min) and atypical signaling cascade, regulated by a Ca²⁺-calmodulin/proteasome axis, which induces the nuclear translocation of p65-p50 heterodimer, the principal transcription factor of pro-inflammatory NFkB pathway. In the present study, the repertoire of NF-kB pro-inflammatory genes was early monitored after high-glucose stimulation, in rMC1, as compared to cells stimulated with normal glucose or hyper-osmolar mannitol. The occurrence of an early transcriptional upregulation of most stimulated genes was also verified in rat retina cultures isolated from Sprague-Dawley rats. The overall analysis showed that: (i) high glucose triggers a pro-inflammatory polarization of rMC1 much earlier than previously thought and (ii) this early upregulation recapitulates also in rat retinal culture. Importantly, it has emerged a prominent role played by IL-8 in the early stages of hyperglycemic insult, opening to further studies on its role in primary diabetic retinopathy pathogenesis and envisaging the development of novel potential clinical treatments based on IL-8 blockade.