Abstract
Neovascular age-related macular degeneration (nAMD) commonly causes vision loss from aberrant angiogenesis, termed choroidal neovascularization (CNV). Interleukin-6 (IL6) is a pro-inflammatory and pro-angiogenic cytokine that is correlated with AMD progression and nAMD activity. We hypothesize that anti-IL6 therapy is a potential nAMD therapeutic. We found that IL6 levels were increased after laser injury and expressed by macrophages. Il6-deficiency decreased laser-induced CNV area and exogenous IL6 addition increased choroidal sprouting angiogenesis. Il6-null mice demonstrated equally increased macrophage numbers as wildtype mice. At steady state, IL6R expression was detected on peripheral blood and ocular monocytes. After laser injury, the number of IL6R+Ly6C+ monocytes in blood and IL6R+ macrophages in the eye were increased. In human choroid, macrophages expressed IL6, IL6R, and IL6ST. Furthermore, IL6R+ macrophages displayed a transcriptional profile consistent with STAT3 (signal transducer and activator of transcription 3) activation and angiogenesis. Our data show that IL6 is both necessary and sufficient for choroidal angiogenesis. Macrophage-derived IL6 may stimulate choroidal angiogenesis via classical activation of IL6R+ macrophages, which then stimulate angiogenesis. Targeting IL6 or the IL6R could be an effective adjunctive therapy for treatment-resistant nAMD patients.
Highlights
Neovascular age-related macular degeneration commonly causes vision loss from aberrant angiogenesis, termed choroidal neovascularization (CNV)
The number of I L6R+Ly6C+ monocytes increased in peripheral blood, and IL6 receptor (IL6R)+ macrophages were detected in the eye
Because macrophages produce IL6 and classical monocyte-derived macrophages are necessary for CNV pathogenesis[11,12], we examined macrophage numbers after laser injury
Summary
Neovascular age-related macular degeneration (nAMD) commonly causes vision loss from aberrant angiogenesis, termed choroidal neovascularization (CNV). Several other labs, have demonstrated that beta-adrenergic receptor blockade inhibits experimental CNV by 50–80%3–8. Patients with treatment-resistant nAMD received continued monthly anti-VEGF injections plus either placebo or topical dorzolamide-timolol (carbonic anhydrase inhibitor plus beta-adrenergic receptor blocker). Adjuvant topical dorzolamide-timolol significantly reduced persistent retinal fluid compared to p lacebo[9], an important finding to help reduce anti-VEGF injection burden Despite these results, the mechanism by which beta-adrenergic receptor blockade inhibits CNV remains unknown. Classical monocyte-derived macrophages are necessary for propranolol-driven CNV b lockade[6], and propranolol decreases IL6 levels during experimental CNV3,4. The number of I L6R+Ly6C+ monocytes increased in peripheral blood, and IL6R+ macrophages were detected in the eye. Human choroidal macrophages expressed IL6 and the IL6R. IL6R+ human macrophages showed a transcriptional profile consistent with signal transducer and Scientific Reports | (2021) 11:18084
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
