期刊
FASEB JOURNAL
卷 35, 期 8, 页码 -出版社
WILEY
DOI: 10.1096/fj.202100686R
关键词
corneal nerves; hgf; pain; Rictor; RvD6 stereoisomers; trigeminal ganglia transcriptome
资金
- National Institutes of Health [R01EY019465]
- National Eye Institute
Innervation is crucial for maintaining cornea integrity. The combination of PEDF and DHA can stimulate the synthesis of a new stereoisomer of RvD6si, which promotes nerve regeneration. RR-RvD6 is more potent than SR-RvD6 in increasing cornea sensitivity and nerve regeneration, indicating a novel function of this lipid mediator in maintaining cornea integrity and homeostasis after injury.
Innervation sustains cornea integrity. Pigment epithelium-derived factor (PEDF) plus docosahexaenoic acid (DHA) regenerated damaged nerves by stimulating the synthesis of a new stereoisomer of Resolvin D6 (RvD6si). Here, we resolved the structure of this lipid isolated from mouse tears after injured corneas were treated with PEDF + DHA. RvD6si synthesis was inhibited by fluvoxamine, a cytochrome P450 inhibitor, but not by 15- or 5-LOX inhibitors, suggesting that the 4- and 17-hydroxy of DHA have an RR- or SR-configuration. The two compounds were chemically synthesized. Using chiral phase HPLC, four peaks of RvD6si(1-4) from tears were resolved. The RR-RvD6 standard eluted as a single peak with RvD6(1) while pure SR-RvD6 eluted with RvD6(3). The addition of these pure mediators prompted a trigeminal ganglion transcriptome response in injured corneas and showed that RR-RvD6 was the more potent, increasing cornea sensitivity and nerve regeneration. RR-RvD6 stimulates Rictor and hepatocyte growth factor (hgf) genes specifically as upstream regulators and a gene network involved in axon growth and suppression of neuropathic pain, indicating a novel function of this lipid mediator to maintain cornea integrity and homeostasis after injury.
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