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Microglial cGAS-STING signaling underlies glaucoma pathogenesis.
Liu, Yutong; Wang, Ailian; Chen, Chen; Zhang, Qian; Shen, Qin; Zhang, Dan; Xiao, Xueqi; Chen, Shasha; Lian, Lili; Le, Zhenmin; Liu, Shengduo; Liang, Tingbo; Zheng, Qinxiang; Xu, Pinglong; Zou, Jian.
Afiliación
  • Liu Y; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • Wang A; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Chen C; Ministry of Education Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • Zhang Q; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • Shen Q; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Zhang D; Ministry of Education Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • Xiao X; Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, University School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • Chen S; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Lian L; Ministry of Education Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • Le Z; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Liu S; Ministry of Education Laboratory of Biosystems Homeostasis and Protection, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • Liang T; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Zheng Q; Institute of Intelligent Medicine, Zhejiang University-Hangzhou Global Scientific and Technological Innovation Center, Hangzhou 310058, China.
  • Xu P; Eye Center of the Second Affiliated Hospital School of Medicine, Center for Genetic Medicine, Zhejiang University International Institute of Medicine, Hangzhou 310029, China.
  • Zou J; College of Life and Environmental Science, Wenzhou University, Wenzhou 325035, China.
Proc Natl Acad Sci U S A ; 121(36): e2409493121, 2024 Sep 03.
Article en En | MEDLINE | ID: mdl-39190350
ABSTRACT
Characterized by progressive degeneration of retinal ganglion cells (RGCs) and vision loss, glaucoma is the primary cause of irreversible blindness, incurable and affecting over 78 million patients. However, pathogenic mechanisms leading to glaucoma-induced RGC loss are incompletely understood. Unexpectedly, we found that cGAS-STING (2'3'-cyclic GMP-AMP-stimulator of interferon genes) signaling, which surveils displaced double-stranded DNA (dsDNA) in the cytosol and initiates innate immune responses, was robustly activated during glaucoma in retinal microglia in distinct murine models. Global or microglial deletion of STING markedly relieved glaucoma symptoms and protected RGC degeneration and vision loss, while mice bearing genetic cGAS-STING supersensitivity aggravated retinal neuroinflammation and RGC loss. Mechanistically, dsDNA from tissue injury activated microglial cGAS-STING signaling, causing deleterious macroglia reactivity in retinas by cytokine-mediated microglia-macroglia interactions, progressively driving apoptotic death of RGCs. Remarkably, preclinical investigations of targeting cGAS-STING signaling by intraocular injection of TBK1i or anti-IFNAR1 antibody prevented glaucoma-induced losses of RGCs and vision. Therefore, we unravel an essential role of cGAS-STING signaling underlying glaucoma pathogenesis and suggest promising therapeutic strategies for treating this devastating disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Glaucoma / Microglía / Proteínas de la Membrana / Nucleotidiltransferasas Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Glaucoma / Microglía / Proteínas de la Membrana / Nucleotidiltransferasas Límite: Animals Idioma: En Revista: Proc Natl Acad Sci U S A Año: 2024 Tipo del documento: Article País de afiliación: China Pais de publicación: Estados Unidos