title: STAT3 Activation in Circulating Monocytes Contributes to Neovascular Age-Related Macular Degeneration.
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.
authors.affiliation: Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK. m.chen@qub.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Chen
authors.forename: J
authors.initials: J
authors.lastname: Lechner
authors.forename: J
authors.initials: J
authors.lastname: Zhao
authors.forename: L
authors.initials: L
authors.lastname: Toth
authors.forename: R
authors.initials: R
authors.lastname: Hogg
authors.forename: G
authors.initials: G
authors.lastname: Silvestri
authors.forename: A
authors.initials: A
authors.lastname: Kissenpfennig
authors.forename: U
authors.initials: U
authors.lastname: Chakravarthy
authors.affiliation: Wellcome-Wolfson Institute of Experimental Medicine, Queen's University Belfast, 97 Lisburn Road, Belfast, BT9 7BL, UK. heping.xu@qub.ac.uk.
authors.forename: H
authors.initials: H
authors.lastname: Xu
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D015153:Blotting, Western; D016022:Case-Control Studies; D020256:Choroidal Neovascularization / Q000378:metabolism / Q000473:pathology; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D007834:Lasers; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D019707:Receptors, Chemokine / Q000378:metabolism; D012160:Retina / Q000187:drug effects / Q000473:pathology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism; D057135:Wet Macular Degeneration / Q000097:blood* / Q000473:pathology*
chemical_list: D000880:Anthraquinones; D006684:HLA-DR Antigens; C549232:LLL12 compound; D019707:Receptors, Chemokine; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D013449:Sulfonamides; D000071223:Suppressor of Cytokine Signaling 3 Protein