IL10-driven STAT3 signalling in senescent macrophages promotes pathological eye angiogenesis

Rei Nakamura, Abdoulaye Sene, Andrea Santeford, Abdelaziz Gdoura, Shunsuke Kubota, Nicole Zapata and Rajendra S. Apte ()
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Rei Nakamura: Washington University School of Medicine
Abdoulaye Sene: Washington University School of Medicine
Andrea Santeford: Washington University School of Medicine
Abdelaziz Gdoura: Washington University School of Medicine
Shunsuke Kubota: Washington University School of Medicine
Nicole Zapata: Washington University School of Medicine
Rajendra S. Apte: Washington University School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms8847

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