Blockade of interleukin-6 trans-signaling prevents mitochondrial dysfunction and cellular senescence in retinal endothelial cells

Jessica M Hoffman; Rebekah Robinson; Grace Greenway; Joshua Glass; Stepan Budkin; Shruti Sharma

doi:10.1016/j.exer.2023.109721

Blockade of interleukin-6 trans-signaling prevents mitochondrial dysfunction and cellular senescence in retinal endothelial cells

Exp Eye Res. 2023 Dec:237:109721. doi: 10.1016/j.exer.2023.109721. Epub 2023 Nov 11.

Authors

Jessica M Hoffman¹, Rebekah Robinson², Grace Greenway², Joshua Glass², Stepan Budkin², Shruti Sharma³

Affiliations

¹ Department of Biological Sciences, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: jehoffman@augusta.edu.
² Center for Biotechnology and Genomic Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA.
³ Center for Biotechnology and Genomic Medicine, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA; Department of Ophthalmology, Augusta University, 1120 15th Street, Augusta, GA, 30912, USA. Electronic address: shsharma@augusta.edu.

PMID: 37956941
PMCID: PMC10759313 (available on 2024-12-01)
DOI: 10.1016/j.exer.2023.109721

Abstract

Interleukin-6 (IL-6) is a multifaceted cytokine implicated in the pathogenesis of diabetic retinopathy (DR). Its activity extends through cis- and trans-signaling (TS) pathways, with cis-signaling limited to specific cell types possessing the membrane-bound IL-6 receptor, while trans-signaling broadly activates various cells without the membrane bound IL-6 receptor, including retinal endothelial cells. In this study, we determined the effects of interleukin-6 trans-signaling on mitochondrial dysfunction and cellular senescence in human retinal endothelial cells (HRECs). HRECs were cultured and treated with IL-6 + soluble IL-6R or Hyper IL-6 to activate trans-signaling, along with sgp130Fc for inhibition. RT-PCR was used to analyze gene expression changes associated with inflammation and senescence. Cellular senescence was assessed using SA β-gal staining. Mitochondrial function was evaluated using Seahorse XFe24 Bioanalyzer. IL-6 trans-signaling induced inflammatory gene expression as indicated by the upregulation of ICAM1, MCP1, and SERPINA3 levels. Additionally, it reduced mitochondrial respiration and oxidative phosphorylation, and these effects were counteracted by sgp130Fc. Moreover, IL-6 trans-signaling led to altered expression of apoptosis-associated genes, including downregulation of FIS1, BCL2, and MCL1, while promoting cellular senescence, a phenomenon mitigated by sgp130Fc. These results not only deepen our understanding of IL-6 in DR but also carry broader implications for age-related diseases and the aging process itself. This study underscores the potential therapeutic value of targeting IL-6 trans-signaling with sgp130Fc as a promising anti-inflammatory approach for DR and potentially other inflammatory conditions. Further in-vivo investigations are warranted to elucidate the function of IL-6 trans-signaling in aging-related pathologies and overall organismal health.

Keywords: IL-6 trans-signaling; endothelial cells; mitochondrial dysfunction; senescence.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Cellular Senescence
Endothelial Cells* / metabolism
Humans
Interleukin-6* / metabolism
Mitochondria / metabolism
Receptors, Interleukin-6 / metabolism

Substances

Interleukin-6
Receptors, Interleukin-6
IL6 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding