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.
| Original language | English (US) |
|---|---|
| Article number | 18084 |
| Journal | Scientific reports |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2021 |
Funding
CMC was supported by a Lupus Research Alliance Novel Research Grant, a Rheumatology Research Foundation Innovative Research Award, and a Northwestern University Dixon Translational Research Grant Initiative Award. HP was supported by NIH grant AR064546, HL134375, AG049665, UH2AR067687, the United States-Israel Binational Science Foundation (2013247), and the Rheumatology Research Foundation (Agmt 05/06/14). HP was also supported by the Mabel Greene Myers Professor of Medicine and generous donations to the Rheumatology Precision Medicine Fund. JAL was supported by NIH grant K08 EY030923 and the Research to Prevent Blindness Sybil B. Harrington Career Development Award for Macular Degeneration. This study was supported by an Unrestricted Departmental Grant from Research to Prevent Blindness. Imaging work was performed at the Northwestern University Center for Advanced Microscopy generously supported by CCSG P30 CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. RNA Scope and immunohistochemistry services were provided by the Northwestern University Research Histology and Phenotyping Laboratory which is supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center. No funding body had any role in the design of the study, collection, analysis, interpretation of data, or in writing the manuscript.
ASJC Scopus subject areas
- General