AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ1−40-Induced retinal pigment epithelium injury

作者：Xiaoxu Huang, Tongqi Li, Guanran Zhang, Jieqiong Chen, Tong Li, Shiqi Yang, Qiyu Bo, Xiaohuan Zhao, Xiaoling Wan, Xinyue Zhu, Bo Yu, Xiaodong Sun, Junran Sun · 发表于：Cell Communication and Signaling · 年份：2025 · DOI：10.1186/s12964-025-02294-w · 被引用次数：7 · 研究领域：Inflammasome and immune disorders、Ocular Diseases and Behçet’s Syndrome、Alzheimer's disease research and treatments

The retinal pigment epithelium (RPE) degeneration and subsequent retinal atrophy are hallmarks of age-related macular degeneration (AMD). Amyloid-beta (Aβ), the primary component of amyloid plaques in Alzheimer’s disease (AD), is also present within drusen and is considered a critical factor contributing to RPE degeneration in AMD. Recent findings indicate that Aβ-induced inflammation plays a role in RPE degeneration. The aim of this study was to explore the molecular players and the precise mechanisms involved in this process, particularly the potential role of the absent in melanoma 2 (AIM2)-like receptors (ALRs) inflammasome. An animal model of Aβ 1-40 -induced RPE injury was established. Fundus photography, electrophysiology and hematoxylin-eosin staining were used to evaluate the morphological and functional RPE damage. Transcriptome sequencing was used to detect the differentially expressed genes between Aβ 1-40 group and control group. The transcriptional and protein expression levels of AIM2 pathway and RIPK family members were detected. Adeno-associated virus vector 2/2 (AAV2/2)-shAIM2 was constructed to knockdown AIM2 expression in mice RPE cells. Aβ 1-40 -treated ARPE-19 cells and hRPE cells were employed to analyze the regulatory effects of RIPK family on mitochondrial DNA (mtDNA) release and AIM2 pathway activation. Aβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits ...