Exercise alleviates neovascular age-related macular degeneration by inhibiting AIM2 inflammasome in myeloid cells

• Published in: Metabolism, clinical and experimental Vol. 144; p. 155584
• Main Authors: Cui, Bohao, Guo, Xu, Zhou, Wei, Zhang, Xiaodan, He, Kai, Bai, Tinghui, Lin, Dongxue, Wei-Zhang, Selena, Zhao, Yan, Liu, Shengnan, Zhou, Hui, Wang, Qing, Yao, Xueming, Shi, Ying, Xie, Ruotian, Dong, Xue, Lei, Yi, Du, Mei, Chang, Yongsheng, Xu, Heping, Zhou, Dongming, Yu, Ying, Wang, Xiaohong, Yan, Hua
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.07.2023
• Subjects: Adiponectin; Age-related macular degeneration; Aged; AIM2 inflammasome; Animals; Anti-angiogenic therapy; Choroidal Neovascularization - drug therapy; Choroidal Neovascularization - etiology; Choroidal Neovascularization - prevention & control; DNA-Binding Proteins; Exercise; Humans; Inflammasomes; Macular Degeneration - complications; Macular Degeneration - metabolism; Macular Degeneration - therapy; Mice; Myeloid Cells - metabolism; Proteomics; Vascular Endothelial Growth Factor A - genetics; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - therapeutic use; Anti-angiogenic therapy; Exercise; Age-related macular degeneration; AIM2 inflammasome; Adiponectin
• ISSN: 0026-0495; 1532-8600
• DOI: 10.1016/j.metabol.2023.155584

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. [Display omitted] •High physical activity levels correlate with improved lesion recovery in AMD patients.•Adiponectin is necessary for the protective effect of exercise on CNV.•AIM2 deficiency improves CNV progression in mice.•Adiponectin suppresses AIM2 activation by reducing p47-mediated ROS production.