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STAT3 Activation in Circulating Monocytes Contributes to Neovascular Age-Related Macular Degeneration
1Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK. m.chen@qub.ac.uk.
Abstract:
Infiltrating macrophages are critically involved in pathogenic angiogenesis such as neovascular agerelated macular degeneration (nAMD). Macrophages originate from circulating monocytes and three subtypes of monocyte exist in humans: classical (CD14(+)CD16(-)), non-classical (CD14(-)CD16(+)) and intermediate (CD14(+)CD16(+)) monocytes. The aim of this study was to investigate the role of circulating monocyte in neovascular age-related macular degeneration (nAMD). Flow cytometry analysis showed that the intermediate monocytes from nAMD patients expressed higher levels of CX3CR1 and HLA-DR compared to those from controls. Monocytes from nAMD patients expressed higher levels of phosphorylated Signal Transducer and Activator of Transcription 3 (pSTAT3), and produced higher amount of VEGF. In the mouse model of choroidal neovascularization (CNV), pSTAT3 expression was increased in the retina and RPE/choroid, and 49.24% of infiltrating macrophages express pSTAT3. Genetic deletion of the Suppressor of Cytokine Signalling 3 (SOCS3) in myeloid cells in the LysM-Cre(+/-):SOCS3(fl/fl) mice resulted in spontaneous STAT3 activation and accelerated CNV formation. Inhibition of STAT3 activation using a small peptide LLL12 suppressed laserinduced CNV. Our results suggest that monocytes, in particular the intermediate subset of monocytes are activated in nAMD patients. STAT3 activation in circulating monocytes may contribute to the development of choroidal neovascularisation in AMD.
Insights
Intermediate monocytes are activated in neovascular age-related macular degeneration (nAMD). STAT3 activation in these monocytes contributes to choroidal neovascularization, a key factor in AMD progression.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Infiltrating macrophages drive pathogenic angiogenesis in conditions like neovascular age-related macular degeneration (nAMD).
- Human monocytes comprise three subtypes: classical, non-classical, and intermediate.
Purpose of the Study:
- To investigate the specific role of circulating monocyte subtypes in nAMD.
- To explore the involvement of Signal Transducer and Activator of Transcription 3 (STAT3) signaling in nAMD pathogenesis.
Main Methods:
- Flow cytometry was used to analyze monocyte subsets (CD14, CD16) and marker expression (CX3CR1, HLA-DR) in nAMD patients versus controls.
- Quantification of phosphorylated STAT3 (pSTAT3) and vascular endothelial growth factor (VEGF) in monocytes.
- A mouse model of choroidal neovascularization (CNV) was employed to study pSTAT3 expression in vivo.
- Genetic manipulation (SOCS3 deletion) and pharmacological inhibition (LLL12 peptide) of STAT3 were performed.
Main Results:
- Intermediate monocytes from nAMD patients showed increased CX3CR1 and HLA-DR expression.
- Monocytes from nAMD patients exhibited higher pSTAT3 levels and VEGF production.
- In a mouse CNV model, pSTAT3 was elevated in retinal and RPE/choroid tissues, with 49.24% of infiltrating macrophages expressing pSTAT3.
- SOCS3 deletion accelerated CNV, while STAT3 inhibition suppressed laser-induced CNV.
Conclusions:
- Intermediate monocytes are activated in nAMD patients.
- STAT3 activation in circulating monocytes is implicated in the development of choroidal neovascularization in AMD.
- Targeting STAT3 signaling presents a potential therapeutic strategy for nAMD.
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