期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 11, 页码 -出版社
MDPI
DOI: 10.3390/ijms22115833
关键词
receptor for advanced glycosylation end products; advanced glycation end products; corneal endothelial cell; toll-like receptor 9; herpes simplex virus
资金
- Japanese Ministry of Education, Science, and Culture [15K15635, 17K11481]
Senescence, sterile inflammation, and infection can lead to dysfunction of corneal endothelial cells, requiring corneal transplantation. Corneal endothelial cells respond to HSV-1 infection by activating interferon responses, with RAGE playing a key role as a sensor.
Senescence, sterile inflammation, and infection cause dysfunction of corneal endothelial cells, leading to visual morbidity that may require corneal transplantation. With increasing age, the extracellular matrix is modified by non-enzymatic glycation forming advanced glycation end products (AGEs). The modifications are primarily sensed by the receptors for the AGEs (RAGE) and are manifested as a type I interferon response. Interestingly, in our study, human corneal endothelial cells (HCEn) cells did not respond to the typical RAGE ligands, including the AGEs, high mobility group box 1 (HMGB1), and serum amyloid-A (SAA). Instead, HCEn cells responded exclusively to the CpG DNA, which is possessed by typical corneal pathogen, herpes simplex virus-1 (HSV-1). Upon HSV-1 infection, the surface expression of RAGE was increased, and endocytosed HSV-1 was associated with RAGE and CpG DNA receptor, TLR9. RAGE DNA transfection markedly increased interferon-beta secretion by CpG DNA or HSV-1 infection. HSV-1 infection-induced interferon-beta secretion was abolished by TLR9 inhibition and partially by RAGE inhibition. Global transcriptional response analysis confirmed that RAGE and TLR9 were both significantly involved in type I interferon responses. We conclude that RAGE is a sensor of HSV-1 infection and provokes a type I interferon response.
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