cGAS drives noncanonical-inflammasome activation in age-related macular degeneration.
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Geographic atrophy is a blinding form of age-related macular degeneration characterized by retinal pigmented epithelium (RPE) death; the RPE also exhibits 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 mouse models is driven by a noncanonical-inflammasome pathway that activates caspase-4 (caspase-11 in mice) and caspase-1, and requires cyclic GMP-AMP synthase (cGAS)-dependent interferon- production and gasdermin D-dependent interleukin-18 secretion. Decreased DICER1 levels or Alu-RNA accumulation triggers cytosolic escape of mitochondrial DNA, which engages cGAS. Moreover, caspase-4, gasdermin D, interferon-, and cGAS levels were elevated in the RPE in human eyes with geographic atrophy. Collectively, these data highlight an unexpected role of cGAS in responding to mobile-element transcripts, reveal cGAS-driven interferon signaling as a conduit for mitochondrial-damage-induced inflammasome activation, expand the immune-sensing repertoire of cGAS and caspase-4 to noninfectious human disease, and identify new potential targets for treatment of a major cause of blindness.
author list (cited authors)
Kerur, N., Fukuda, S., Banerjee, D., Kim, Y., Fu, D., Apicella, I., ... Ambati, J.
complete list of authors
Kerur, Nagaraj||Fukuda, Shinichi||Banerjee, Daipayan||Kim, Younghee||Fu, Dongxu||Apicella, Ivana||Varshney, Akhil||Yasuma, Reo||Fowler, Benjamin J||Baghdasaryan, Elmira||Marion, Kenneth M||Huang, Xiwen||Yasuma, Tetsuhiro||Hirano, Yoshio||Serbulea, Vlad||Ambati, Meenakshi||Ambati, Vidya L||Kajiwara, Yuji||Ambati, Kameshwari||Hirahara, Shuichiro||Bastos-Carvalho, Ana||Ogura, Yuichiro||Terasaki, Hiroko||Oshika, Tetsuro||Kim, Kyung Bo||Hinton, David R||Leitinger, Norbert||Cambier, John C||Buxbaum, Joseph D||Kenney, M Cristina||Jazwinski, S Michal||Nagai, Hiroshi||Hara, Isao||West, A Phillip||Fitzgerald, Katherine A||Sadda, SriniVas R||Gelfand, Bradley D||Ambati, Jayakrishna