期刊
INVESTIGATIVE OPHTHALMOLOGY & VISUAL SCIENCE
卷 57, 期 4, 页码 1506-1517出版社
ASSOC RESEARCH VISION OPHTHALMOLOGY INC
DOI: 10.1167/iovs.16-19134
关键词
microRNA; Pseudomonas aeruginosa-induced keratitis; miR-183/96/182; innate immunity; sensory innervations
资金
- National Eye Institute, National Institutes of Health [R01EY016058, R01EY023226, P30EY004068]
- Research to Prevent Blindness
- Alcon Research award
PURPOSE. The microRNA-183/96/182 cluster (miR-183/96/182) plays important roles in sensory organs. Because the cornea is replete with sensory innervation, we hypothesized that miR-183/96/182 modulates the corneal response to bacterial infection through regulation of neuroimmune interactions. METHODS. Eight-week-old miR-183/96/182 knockout (ko) mice and their wild-type littermates (wt) were used. The central cornea of anesthetized mice was scarred and infected with Pseudomonas aeruginosa (PA), strain 19660. Corneal disease was graded at 1, 3, and 5 days postinfection (dpi). Corneal RNA was harvested for quantitative RT-PCR. Polymorphonuclear neutrophils (PMN) were enumerated by myeloperoxidase assays; the number of viable bacteria was determined by plate counts, and ELISA assays were performed to determine cytokine protein levels. A macrophage (M phi) cell line and elicited peritoneal PMN were used for in vitro functional assays. RESULTS. MicroRNA-183/96/182 is expressed in the cornea, and in M phi and PMN of both mice and humans. Inactivation of miR-183/96/182 resulted in decreased corneal nerve density compared with wt mice. Overexpression of miR-183/96/182 in M phi decreased, whereas knockdown or inactivation of miR-183/96/182 in M phi and PMN increased their capacity for phagocytosis and intracellular killing of PA. In PA-infected corneas, ko mice showed decreased proinflammatory neuropeptides such as substance P and chemoattractant molecules, MIP-2, MCP1, and ICAM1; decreased number of PMN at 1 and 5 dpi; increased viable bacterial load at 1 dpi, but decreased at 5 dpi; and markedly decreased corneal disease. CONCLUSIONS. MicroRNA-183/96/182 modulates the corneal response to bacterial infection through its regulation of corneal innervation and innate immunity.
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