ArticleCell communication and signaling : CCS2025
AIM2 activation mediated by RIPK1/3-dependent mitochondrial DNA release drives Aβ
Article in Cell communication and signaling : CCS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- The Molecular Basis of Ocular Aging: Mechanisms, Pathologies, and Emerging Therapeutics.Investigative ophthalmology & visual science · 2026Review
- Spatiotemporal regulation of acute wound healing by the NLRP3 inflammasome: dual roles in macrophage-fibroblast chemotaxis and phenotype during wound repair.Burns & trauma · 2026Article
- Prominin-1 Regulates Retinal Pigment Epithelium Homeostasis: Transcriptomic Insights into Degenerative Mechanisms.International journal of molecular sciences · 2025Article
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Authors and funding
13 authors.
Funding
Abstract
backgroundThe 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.
methodsAn animal model of Aβ
resultsAβ induces RPE damage through stimulation of AIM2 inflammasome and augmentation of caspase-1 and interleukin-1β (IL-1β). Knocking down AIM2 inhibits the release of inflammatory cytokines and alleviates the degeneration of the retina and RPE. Simultaneously, Aβ triggers the activation of RIPK1/RIPK3 kinases, as manifested by heightened protein expression and phosphorylation. Inhibiting RIPK1/RIPK3 phosphorylation dampens AIM2 inflammasome activity and curtails IL-1β secretion. Mechanistically, RIPK1/RIPK3 inhibition attenuates Aβ-induced Drp1(S616) hyperphosphorylation, consequently reducing mitochondrial fission and the efflux of mitochondrial DNA (mtDNA) into the cytosol. The diminished mtDNA release is responsible for attenuated AIM2 activation and subsequent inactivation of the stimulator of interferon genes (STING)/nuclear factor-kappa-B (NF-κB) signaling cascade.
conclusionsOur study is the first to validate AIM2's contribution in Aβ-induced RPE pathology and underscore the significance of the RIPK1/RIPK3-induced mtDNA release in modulating inflammatory responses, shedding light on the underlying mechanisms and potential therapeutics of AMD.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.