Retinal glia and NF-κB in diabetic retinopathy pathogenesis

Diabetic retinopathy (DR) is a leading cause of irreversible blindness in adults (1-3). Treatments available to limit vision loss from complications of DR include intravitreal injection of drugs that inhibit vascular endothelial growth factor (VEGF) or inflammation, surgery and retinal laser photocoagulation (3). Despite these interventions, blindness from DR persists since the retinal vasculopathy and neuronal degeneration cannot be reversed.

Extensive research has been conducted to decipher the molecular pathways involved in the development of DR in the hopes of finding a cure. Oxidative stress and inflammation are important pathways activated in DR (3). Recent studies indicate that neurodegeneration of retinal ganglion cells and glial cell activation occur before development of retinal vasculopathy and are important early steps involved in the pathogenesis of DR (4). Glial cell activation triggers inflammation and oxidative stress, which in turn worsens DR.

In the publication by Ding et al., retinal glia was targeted to limit retinal neuronal degeneration from DR (5). Muller cells are the principal retinal glial cells that stretch across the thickness of the retina and provide homeostatic and metabolic support to neurons by mediating transcellular ion, water and bicarbonate transport (6). They are components of the neurovascular unit in the retina, regulating the blood-retinal barrier and synaptic activity of retinal neurons. Microglia are resident immune cells contributing to immune surveillance. Microglia, activated by retinal injury, produce proinflammatory mediators and kill degenerating retinal neurons (7). Targeting the retinal glia to limit retinal damage from DR is a novel, logical approach.

Ding et al. used a rat model of DR to study the effect of inhibition of nuclear factor-κB (NF-κB) activation via systemic administration of IMD-0354 (5) since NF-κB is a transcription factor that regulates the activation of microglia and Muller cells (8). In addition, in vitro studies were conducted using cultured retinal glial cells to evaluate the effects of IMD-0354. The authors found that the increase in nuclear NF-κB-p65 associated with DR was reduced by IMD-0354 administration. IMD-0354 also inhibited microglia and Muller cell activation and oxidative damage and apoptosis of the retinal neurons associated with DR. Decreased retinal production of VEGF and inflammatory cytokines was also observed. In vitro studies similarly showed that IMD-0354 inhibited the molecular changes associated with high glucose in cultured Muller cells and microglia.

The study findings are compelling although many questions remain unanswered. What are long-term effects of inhibiting NF-κB activation on retinal function and development of DR? Since NF-κB is ubiquitously expressed, is systemic inhibition of this factor well tolerated? Since the pathogenesis of DR is complex, further investigation is needed regarding the role of NF-κB and glia in the development of DR.

Acknowledgments

Funding: This work was supported in part by the Barbara A. & Alan M. Roth, MD Endowed Chair of Discovery, Education and Patient Care in Vision Science (SS Park) from the University of California Davis.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Annals of Translational Medicine. The article did not undergo external peer review.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-23-1166/coif). The author reports contracted research to employer for multicenter clinical trial from industry evaluating intravitreal drugs that inhibit VEGF or inflammation to treat retinopathy. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Cheung N, Mitchell P, Wong TY. Diabetic retinopathy. Lancet 2010;376:124-36. [Crossref] [PubMed]
2. Yau JW, Rogers SL, Kawasaki R, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 2012;35:556-64. [Crossref] [PubMed]
3. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond) 2015;2:17. [Crossref] [PubMed]
4. Rolev KD, Shu XS, Ying Y. Targeted pharmacotherapy against neurodegeneration and neuroinflammation in early diabetic retinopathy. Neuropharmacology 2021;187:108498. [Crossref] [PubMed]
5. Ding X, Sun Z, Guo Y, et al. Inhibition of NF-κB ameliorates aberrant retinal glia activation and inflammatory responses in streptozotocin-induced diabetic rats. Ann Transl Med 2023;11:197. [Crossref] [PubMed]
6. Reichenbach A, Bringmann A. New functions of Müller cells. Glia 2013;61:651-78. [Crossref] [PubMed]
7. Fan W, Huang W, Chen J, et al. Retinal microglia: Functions and diseases. Immunology 2022;166:268-86. [Crossref] [PubMed]
8. Palazzo I, Todd LJ, Hoang TV, et al. NFkB-signaling promotes glial reactivity and suppresses Müller glia-mediated neuron regeneration in the mammalian retina. Glia 2022;70:1380-401. [Crossref] [PubMed]