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Updated: Jan 17, 2026
Efficient Derivation of Retinal Pigment Epithelium Cells from Stem Cells
Published on: March 8, 2015
Targeting RPE Senescence Via Suppressing IL-6/IL-6R Signaling for Treating Retinal Degenerative Diseases
Tian Zhou1,2, Ziqi Yang1,2, Biyan Ni1,2
1State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, People's Republic of China.
Purpose:
Progressive dysfunction of retinal pigment epithelium (RPE) cells is a crucial factor for retinal degeneration, leading to irreversible blindness with limited therapeutic options. Cellular senescence of RPE cells and inflammation are important hallmarks for retinal degeneration, but the underlying molecular mechanisms and potential interventions remain largely unexplored. This study aims to explore whether the IL-6/ IL-6R axis establishes a senescence-inducing circuit in RPE cells, and to evaluate the therapeutic efficacy of its inhibition in rescuing senescent RPE cells and degenerative retina.
Methods:
Sodium iodate (NaIO₃)-induced retinal degeneration mouse models were established and subjected to intravitreal injections of IL-6 neutralizing antibody, or an IL-6R inhibitor tocilizumab, respectively. Conditional deletion of Stat3 in RPE cells was achieved via subretinal delivery of AAV vectors. RPE cells were isolated for single-cell RNA sequencing (scRNA-seq), qPCR, Western blotting, and immunofluorescence staining. Retinal structure and function were assessed using optical coherence tomography (OCT), hematoxylin and eosin (H&E) staining, and electroretinography (ERG).
Results:
RPE underwent cellular senescence in NaIO3-induced degeneration, which was dependent on activation of the IL-6/IL-6R axis. IL-6 promoted the senescence of RPE and exacerbated retinal degeneration. In contrast, inhibition of IL-6 suppressed RPE senescence and facilitated recovery of retinal structure and function. Mechanistically, STAT3 activation was essential for IL-6-mediated cellular senescence. Notably, tocilizumab effectively blocked the IL-6/IL-6R/STAT3 signaling cascade, attenuated RPE senescence, and protected against retinal degeneration, expanding the indications of tocilizumab.
Conclusions:
IL-6 and IL-6R/STAT3 signaling played an essential role in RPE senescence, and tocilizumab presents a translational opportunity in treating retinal degenerative diseases.
Insights
Interleukin-6 (IL-6) signaling drives retinal pigment epithelium (RPE) cell senescence and degeneration. Inhibiting IL-6 or its receptor (IL-6R) with tocilizumab rescues senescent RPE cells and protects against retinal degeneration.
Area of Science:
- Ophthalmology
- Cellular Biology
- Immunology
Background:
- Progressive retinal pigment epithelium (RPE) cell dysfunction is a key driver of retinal degeneration and blindness.
- Cellular senescence and inflammation in RPE cells are hallmarks of retinal degeneration, but underlying mechanisms are not fully understood.
Purpose of the Study:
- To investigate if the IL-6/IL-6R axis induces RPE cell senescence.
- To evaluate the therapeutic potential of inhibiting this axis in RPE senescence and retinal degeneration.
Main Methods:
- Established sodium iodate-induced retinal degeneration mouse models.
- Administered IL-6 neutralizing antibody or tocilizumab (IL-6R inhibitor).
- Assessed RPE senescence, retinal structure, and function using molecular and imaging techniques.
Main Results:
- RPE senescence was observed in NaIO₃-induced degeneration, dependent on the IL-6/IL-6R axis.
- IL-6 exacerbated RPE senescence and retinal degeneration; IL-6 inhibition promoted recovery.
- STAT3 activation was crucial for IL-6-induced RPE senescence; tocilizumab blocked this pathway.
Conclusions:
- The IL-6/IL-6R/STAT3 pathway is critical for RPE senescence.
- Tocilizumab demonstrates therapeutic potential for treating retinal degenerative diseases by mitigating RPE senescence.
