Nana Xu1,2, Qiyu Bo1,2, Rong Shao3,4, Jian Liang5, Yuanqi Zhai5, Shiqi Yang1,2, Fenghua Wang1,2, Xiaodong Sun1,2,5. 1. Department of Ophthalmology, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. 2. Shanghai Engineering Center for Visual Science and Photomedicine, Shanghai, China. 3. Depatrtment of Pharmacology, Shanghai Jiao Tong University School of Medicine Shanghai, China. 4. Department of Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. 5. Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China.
Abstract
Purpose: Choroidal neovascularization (CNV) is the principal pathological factor contributing to blindness in neovascular age-related macular degeneration (nAMD). Infiltration of M2 macrophage is thought to contribute to CNV progress, although the way that regulates its differentiation remains unclear. Here, we investigate the role of CHI3L1 in M2 differentiation and angiogenesis in CNV. Methods: Serums from nAMD patients were tested for CHI3L1 expression. Mice were subjected to laser injury to induce CNV, and lesion expansion were tracked using fundus fluorescence angiography (FFA) and immunofluorescence analysis. Several strategies were taken to verify the contribution of M2 macrophage and CHI3L1: macrophage depletion by clodrosome, local CHI3L1 inhibition using intravitreally injection neutralize antibody (mAY), and depletion of CHI3L1 receptor (IL13-Ra2) by small-interfering RNA (siRNA). Tuber analysis was used to further determine angiogenetic effect of CHI3L1. Anti-VEGFA was used as positive control for mAY. Results: Serum levels of CHI3L1 were highly elevated in nAMD patients. CHI3L1 was expressed by infiltrating M2 macrophages and was elevated as CNV progress in a mice model. System macrophage depletion and local suppression of CHI3L1 alleviated CNV formation while enhancing anti-VEGFA therapeutic effect. Stimulation of macrophage with recombinant CHI3L1 activated MAPK signaling cascade and induced transition to M2, while siRNA knockdown of IL13-Ra2 abolished it. In an in vitro coculture system, supernatants from CHI3L1-stimulated M2 macrophages and promoted tube vascularization. Conclusions: These results unveil novel angiogenic regulation of CHI3L1 and M2 polarized macrophages in CNV development. These mechanistic insights may point to CHI3L1 as a new therapeutic target for treatment for nAMD.
Purpose: Choroidal neovascularization (CNV) is the principal pathological factor contributing to blindness in neovascular age-related macular degeneration (nAMD). Infiltration of M2 macrophage is thought to contribute to CNV progress, although the way that regulates its differentiation remains unclear. Here, we investigate the role of CHI3L1 in M2 differentiation and angiogenesis in CNV. Methods: Serums from nAMD patients were tested for CHI3L1 expression. Mice were subjected to laser injury to induce CNV, and lesion expansion were tracked using fundus fluorescence angiography (FFA) and immunofluorescence analysis. Several strategies were taken to verify the contribution of M2 macrophage and CHI3L1: macrophage depletion by clodrosome, local CHI3L1 inhibition using intravitreally injection neutralize antibody (mAY), and depletion of CHI3L1 receptor (IL13-Ra2) by small-interfering RNA (siRNA). Tuber analysis was used to further determine angiogenetic effect of CHI3L1. Anti-VEGFA was used as positive control for mAY. Results: Serum levels of CHI3L1 were highly elevated in nAMD patients. CHI3L1 was expressed by infiltrating M2 macrophages and was elevated as CNV progress in a mice model. System macrophage depletion and local suppression of CHI3L1 alleviated CNV formation while enhancing anti-VEGFA therapeutic effect. Stimulation of macrophage with recombinant CHI3L1 activated MAPK signaling cascade and induced transition to M2, while siRNA knockdown of IL13-Ra2 abolished it. In an in vitro coculture system, supernatants from CHI3L1-stimulated M2 macrophages and promoted tube vascularization. Conclusions: These results unveil novel angiogenic regulation of CHI3L1 and M2 polarized macrophages in CNV development. These mechanistic insights may point to CHI3L1 as a new therapeutic target for treatment for nAMD.
Authors: Apeng Chen; Yinan Jiang; Zhengwei Li; Lingxiang Wu; Ulises Santiago; Han Zou; Chunhui Cai; Vaibhav Sharma; Yongchang Guan; Lauren H McCarl; Jie Ma; Yijen L Wu; Joshua Michel; Yi Shi; Liza Konnikova; Nduka M Amankulor; Pascal O Zinn; Gary Kohanbash; Sameer Agnihotri; Songjian Lu; Xinghua Lu; Dandan Sun; George K Gittes; Qianghu Wang; Xiangwei Xiao; Dean Yimlamai; Ian F Pollack; Carlos J Camacho; Baoli Hu Journal: J Clin Invest Date: 2021-08-16 Impact factor: 14.808
Authors: Yannick van Sleen; William F Jiemy; Sarah Pringle; Kornelis S M van der Geest; Wayel H Abdulahad; Maria Sandovici; Elisabeth Brouwer; Peter Heeringa; Annemieke M H Boots Journal: Arthritis Rheumatol Date: 2021-11-01 Impact factor: 15.483