STAT3 Activation in Circulating Monocytes Contributes to Neovascular Age-Related Macular Degeneration

Abstract

Infiltrating macrophages are critically involved in pathogenic angiogenesis such as neovascular age-related 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+/-:SOCS3fl/fl mice resulted in spontaneous STAT3 activation and accelerated CNV formation. Inhibition of STAT3 activation using a small peptide LLL12 suppressed laser-induced 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.

Plasma markers of chronic low‐grade inflammation in polypoidal choroidal vasculopathy and neovascular age‐related macular degeneration

“…; Chen et al. ,). IL‐10 stimulation of CD8 + cytotoxic T cells lead to secretion of the cytotoxic granzyme B and perforin (Chan et al.…”

“…; Chen et al. ,). One late‐stage clinical manifestation of AMD is the vascular endothelial growth factor (VEGF)‐induced choroidal neovascularizations (CNV).…”

“…Formation of these deposits is a result of an age‐related decline in the efficacy of the retinal tissue and the RPE to handle the constant exposure of reactive oxygen species (Chen et al. ,). Inflammaging is thought to accelerate this process (Khandhadia et al.…”

Contribution of microglia and monocytes to the development and progression of age related macular degeneration

“…In addition, the expression level of the chemokine receptors, CCR1+ or CCR3+, is increased in those that fail to respond to anti‐VEGF therapy, suggesting that systemic immunological factors may have a role in treatment outcome . Consistent with these findings, cytokine expression and release from peripheral blood monocytes isolated from subjects with various types of AMD has also been demonstrated …”

“…63 Consistent with these findings, cytokine expression and release from peripheral blood monocytes isolated from subjects with various types of AMD has also been demonstrated. [64][65][66] The mechanisms by which monocyte changes occur during AMD, and importantly whether the changes contribute to disease progression is not known. One factor that may influence the development of systemic inflammation during AMD are microRNAs.…”