A novel and atypical NF-KB pro-inflammatory program regulated by a CamKII-proteasome axis is involved in the early activation of Muller glia by high glucose

Abstract

Background Diabetic retinopathy (DR) is a microvascular complication of diabetes with a heavy impact on the quality of life of subjects and with a dramatic burden for health and economic systems on a global scale. Although the pathogenesis of DR is largely unknown, several preclinical data have pointed out to a main role of Muller glia (MG), a cell type which spans across the retina layers providing nourishment and support for Retina Ganglion Cells (RGCs), in sensing hyper-glycemia and in acquiring a pro-inflammatory polarization in response to this insult. Results By using a validated experimental model of DR in vitro, rMC1 cells challenged with high glucose, we uncovered the induction of an early (within minutes) and atypical Nuclear Factor-kB (NF-kB) signalling pathway regulated by a calcium-dependent calmodulin kinase II (CamKII)-proteasome axis. Phosphorylation of proteasome subunit Rpt6 (at Serine 120) by CamKII stimulated the accelerated turnover of IkBα (i.e., the natural inhibitor of p65-50 transcription factor), regardless of the phosphorylation at Serine 32 which labels canonical NF-kB signalling. This event allowed the p65-p50 heterodimer to migrate into the nucleus and to induce transcription of IL-8, Il-1β and MCP-1. Pharmacological inhibition of CamKII as well as proteasome inhibition stopped this pro-inflammatory program, whereas introduction of a Rpt6 phospho-dead mutant (Rpt6-S120A) stimulated a paradoxical effect on NF-kB probably through the activation of a compensatory mechanism which may involve phosphorylation of 20S α4 subunit. Conclusions This study introduces a novel pathway of MG activation by high glucose and casts some light on the biological relevance of proteasome post-translational modifications in modulating pathways regulated through targeted proteolysis.

Trimetazidine Affects Mitochondrial Calcium Uniporter Expression to Restore Ischemic Heart Function via Reactive Oxygen Species/NFκB Pathway Inhibition

“…Recently, RNA-Seq analysis and experiments indicated that TMZ inhibited cell apoptosis by downregulating the calmodulin-dependent protein kinase II (CaMK II) pathway after myocardial infarction, 30 whereas in the early activation of Muller glia by high glucose, the induction of an early and atypical NF-κB signaling pathway regulated by CaMK II has been reported. 31 Combined with the evidence of ROS-mediated CaMKII activation, 32 these findings implied a likely ROS/CaMKII/NF-κB apoptosis signaling pathway regulated by TMZ, which may explain the above findings.…”

SOD2 promotes gastric tumorigenesis mediated by Helicobacter pylori and enhances resistance to 5-fluorouracil in gastric cancer

“…SOD2 expression can be regulated by a series of in ammatory cytokines, growth factors, and redox activators via transcriptional and post-transcriptional regulatory mechanisms (Zelko et al 2002). Activation of the NF-κB pathway is a key regulator of in ammation-related tumor progression, and H. pylori infection is thought to generate an in ammatory microenvironment by activating the NF-ĸB pathway (Shalapour and Karin 2015; Lamb et al 2009;Sbardella et al 2022). Our ndings revealed the transcriptional upregulation of SOD2 by NF-κB during H. pylori infection and con rmed crucial NF-κB binding sites in the SOD2 promoter.…”

Eye Diseases: When the Solution Comes from Plant Alkaloids

“…However, 48 hours of berberine treatment restored the rate of phosphorylated AMPK and mTOR, inducing autophagy and inhibiting apoptosis [67]. Nevertheless, the evidence that high glucose levels (typically > 25 mM) may impact the autophagy signaling cascade, but also the ubiquitin-proteasome system (UPS), has been envisaged by studies carried out in rMC1 cells, an immortalized strain of rat Müller cells [70,71]. In 2021, Wang and co-authors proposed that berberine improves the response of retinal endothelial cells to insulin treatment [72].…”