title: IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis.
abstract: Macrophage dysfunction plays a pivotal role during neovascular proliferation in diseases of ageing including cancers, atherosclerosis and blinding eye disease. In the eye, choroidal neovascularization (CNV) causes blindness in patients with age-related macular degeneration (AMD). Here we report that increased IL10, not IL4 or IL13, in senescent eyes activates STAT3 signalling that induces the alternative activation of macrophages and vascular proliferation. Targeted inhibition of both IL10 receptor-mediated signalling and STAT3 activation in macrophages reverses the ageing phenotype. In addition, adoptive transfer of STAT3-deficient macrophages into eyes of old mice significantly reduces the amount of CNV. Systemic and CD163(+) eye macrophages obtained from AMD patients also demonstrate STAT3 activation. Our studies demonstrate that impaired SOCS3 feedback leads to permissive IL10/STAT3 signalling that promotes alternative macrophage activation and pathological neovascularization. These findings have significant implications for our understanding of the pathobiology of age-associated diseases and may guide targeted immunotherapy.
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Rei
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Abdoulaye
authors.initials: A
authors.lastname: Sene
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Santeford
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Gdoura
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kubota
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.
authors.forename: Nicole
authors.initials: N
authors.lastname: Zapata
authors.affiliation: Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, 660 South Euclid Avenue, Box 8096, St Louis, MO 63110, USA.|Department of Developmental Biology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Apte
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000378:metabolism; D000818:Animals; D005123:Eye / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism*; D008264:Macrophages / Q000502:physiology*; D008268:Macular Degeneration / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D011166:Porphyrins; D000067996:RAW 264.7 Cells; D053701:Receptors, Interleukin-10 / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism
chemical_list: C510101:5,15-diphenylporphine; D011166:Porphyrins; D053701:Receptors, Interleukin-10; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D016753:Interleukin-10