2017
DOI: 10.1038/nm.4450
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cGAS drives noncanonical-inflammasome activation in age-related macular degeneration

Abstract: Geographic atrophy is a blinding form of age-related macular degeneration characterized by death of the retinal pigmented epithelium (RPE). In this disease, the RPE displays evidence of DICER1 deficiency, resultant accumulation of endogenous Alu retroelement RNA, and NLRP3 inflammasome activation. How the inflammasome is activated in this untreatable disease is largely unknown. Here we demonstrate that RPE degeneration in human cell culture and in mouse models is driven by a non-canonical inflammasome pathway … Show more

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Cited by 229 publications
(236 citation statements)
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References 82 publications
(147 reference statements)
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“…More recently, Kerur et al 32 reported that GSDMD mediates Alu RNA-induced RPE degeneration, and similar to our study, they did not detect cleaved GSDMD. 32 In contrast, cleavage of GSDME was detected in our study following atRAL-mediated activation of Caspase-3 (Figs. 1E, 1F), suggesting that atRAL induces pyroptosis in ARPE-19 cells via Caspase-3/GSDME activation.…”
Section: Discussionsupporting
confidence: 92%
“…More recently, Kerur et al 32 reported that GSDMD mediates Alu RNA-induced RPE degeneration, and similar to our study, they did not detect cleaved GSDMD. 32 In contrast, cleavage of GSDME was detected in our study following atRAL-mediated activation of Caspase-3 (Figs. 1E, 1F), suggesting that atRAL induces pyroptosis in ARPE-19 cells via Caspase-3/GSDME activation.…”
Section: Discussionsupporting
confidence: 92%
“…In addition, accumulation of cellular mtDNA occurs in age-related macular degeneration characterized by retinal pigmented epithelium (RPE) degeneration. This can trigger chronic inflammation by cGAS-STING pathway, in which NLRP3 inflammasomes, inflammatory/apoptotic caspases are also involved (203,204).…”
Section: Cgas-sting Pathway In Autoimmune or Inflammatory Diseasesmentioning
confidence: 99%
“…Among the para-inflammatory factors, NLR family pyrin domain containing 3 (NLRP3) inflammasome, as a multiprotein complex, recruits NLRP3, ASC, and Caspase-1 to mediate the production of interleukin-1 beta (IL-1β; Yerramothu, Vijay, & Willcox, 2017). More recently, our work Mao et al, 2018;Zhang et al, 2017) and other groups (Kerur & Fukuda, 2018;Kim et al, 2014;Tarallo et al, 2012) indicated excessive recruitment of NLRP3 in retinas could precede RPE damage and retinal degeneration. However, the molecular regulators of NLRP3 in RPE and AMD pathogenesis remain unclear.…”
mentioning
confidence: 84%