PUBLICATION
Microglia-Derived IL-6 Promotes Müller Glia Reprogramming and Proliferation in Zebrafish Retina Regeneration
- Authors
- Xu, J., Li, Y., Li, X., Tan, X., Liu, L., Cao, L., Xu, H.
- ID
- ZDB-PUB-250424-3
- Date
- 2025
- Source
- Investigative ophthalmology & visual science 66: 6767 (Journal)
- Registered Authors
- Xu, Hui
- Keywords
- none
- MeSH Terms
-
- Disease Models, Animal
- Microglia*/metabolism
- Animals, Genetically Modified
- Retina*/physiology
- Zebrafish
- STAT3 Transcription Factor/metabolism
- Cellular Reprogramming*/physiology
- Interleukin-6*/genetics
- Interleukin-6*/metabolism
- Nerve Regeneration*/physiology
- Regeneration*/physiology
- Ependymoglial Cells*/metabolism
- Cell Proliferation/physiology
- Animals
- Signal Transduction
- Zebrafish Proteins/genetics
- PubMed
- 40266594 Full text @ Invest. Ophthalmol. Vis. Sci.
Citation
Xu, J., Li, Y., Li, X., Tan, X., Liu, L., Cao, L., Xu, H. (2025) Microglia-Derived IL-6 Promotes Müller Glia Reprogramming and Proliferation in Zebrafish Retina Regeneration. Investigative ophthalmology & visual science. 66:6767.
Abstract
Purpose Inflammation activates the Jak1-Stat3 signaling pathway in zebrafish Müller glia (MG), leading to their status transition and proliferation following retinal injury. However, the source of Stat3-activating molecules remains unclear. This study aims to explore the expression and function of a Stat3-activating cytokine IL-6 in zebrafish retina regeneration.
Methods Mechanical retinal injury was induced in adult zebrafish by a needle-poke lesion. Single-cell RNA sequencing (scRNAseq) and PCR were used to determine gene expression. Microglia ablation was performed by using the mpeg1:nsfb-mcherry transgenic zebrafish. Morpholino oligonucleotides, a recombinant zebrafish IL-6 protein and drugs, were used to manipulate IL-6 or Stat3 signaling in the retina. The 5-Ethynyl-2'-deoxyuridine (EdU) labeling was used to evaluate MG proliferation and the formation of MG-derived progenitor cells (MGPCs). Neuronal regeneration in the retina was analyzed by lineage tracing and immunostaining.
Results The scRNAseq reveals that IL-6 is mainly expressed by a subset of pro-inflammatory microglia in the injured retina. Loss- and gain-of-function experiments demonstrate that IL-6 signaling promotes MG proliferation and the formation of MGPCs following retinal injury. Additionally, IL-6 facilitates MG status transition by modulating Jak1-Stat3 signaling and the expression of regeneration-associated genes. Interestingly, IL-6 may also regulate MGPC formation via phase-dependent pro-inflammatory and anti-inflammatory mechanisms. Finally, IL-6 promotes the early differentiation of MGPCs and contributes to the regeneration of retinal neurons in the injured retina.
Conclusions Our study unveils the critical role of microglia-derived IL-6 in zebrafish retina regeneration, with potential implications for mammalian MG reprogramming.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping