TY - JOUR
T1 - Exercise alleviates neovascular age-related macular degeneration by inhibiting AIM2 inflammasome in myeloid cells
AU - Cui, Bohao
AU - Guo, Xu
AU - Zhou, Wei
AU - Zhang, Xiaodan
AU - He, Kai
AU - Bai, Tinghui
AU - Lin, Dongxue
AU - Wei-Zhang, Selena
AU - Zhao, Yan
AU - Liu, Shengnan
AU - Zhou, Hui
AU - Wang, Qing
AU - Yao, Xueming
AU - Shi, Ying
AU - Xie, Ruotian
AU - Dong, Xue
AU - Lei, Yi
AU - Du, Mei
AU - Chang, Yongsheng
AU - Xu, Heping
AU - Zhou, Dongming
AU - Yu, Ying
AU - Wang, Xiaohong
AU - Yan, Hua
N1 - Copyright © 2023. Published by Elsevier Inc.
PY - 2023/7
Y1 - 2023/7
N2 - The neovascular form of age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Vascular endothelial growth factor (VEGF) plays a crucial role in choroidal neovascularization (CNV), and anti-VEGF therapy is recommended as first-line therapy for nvAMD. However, many patients do not radically benefit from this therapy. Epidemiological data suggest that physical exercise is beneficial for many human diseases, including nvAMD. Yet, its protective mechanism and therapeutic potential remain unknown. Here, using clinical samples and mouse models, we found that exercise reduced CNV and enhanced anti-angiogenic therapy efficacy by inhibiting AIM2 inflammasome activation. Furthermore, transfusion of serum from exercised mice transferred the protective effects to sedentary mice. Proteomic data revealed that exercise promoted the release of adiponectin, an anti-inflammatory adipokine from adipose tissue into the circulation, which reduced ROS-mediated DNA damage and suppressed AIM2 inflammasome activation in myeloid cells of CNV eyes through AMPK-p47phox pathway. Simultaneous targeting AIM2 inflammasome product IL-1β and VEGF produced a synergistic effect for treating choroidal neovascularization. Collectively, this study highlights the therapeutic potential of an exercise-AMD axis and uncovers the AIM2 inflammasome and its product IL-1β as potential targets for treating nvAMD patients and enhancing the efficacy of anti-VEGF monotherapy.
AB - The neovascular form of age-related macular degeneration (nvAMD) is the leading cause of blindness in the elderly population. Vascular endothelial growth factor (VEGF) plays a crucial role in choroidal neovascularization (CNV), and anti-VEGF therapy is recommended as first-line therapy for nvAMD. However, many patients do not radically benefit from this therapy. Epidemiological data suggest that physical exercise is beneficial for many human diseases, including nvAMD. Yet, its protective mechanism and therapeutic potential remain unknown. Here, using clinical samples and mouse models, we found that exercise reduced CNV and enhanced anti-angiogenic therapy efficacy by inhibiting AIM2 inflammasome activation. Furthermore, transfusion of serum from exercised mice transferred the protective effects to sedentary mice. Proteomic data revealed that exercise promoted the release of adiponectin, an anti-inflammatory adipokine from adipose tissue into the circulation, which reduced ROS-mediated DNA damage and suppressed AIM2 inflammasome activation in myeloid cells of CNV eyes through AMPK-p47phox pathway. Simultaneous targeting AIM2 inflammasome product IL-1β and VEGF produced a synergistic effect for treating choroidal neovascularization. Collectively, this study highlights the therapeutic potential of an exercise-AMD axis and uncovers the AIM2 inflammasome and its product IL-1β as potential targets for treating nvAMD patients and enhancing the efficacy of anti-VEGF monotherapy.
U2 - 10.1016/j.metabol.2023.155584
DO - 10.1016/j.metabol.2023.155584
M3 - Article
C2 - 37150437
SN - 1532-8600
VL - 144
JO - Metabolism: Clinical and Experimental
JF - Metabolism: Clinical and Experimental
M1 - 155584
ER -