July 2018
Volume 59, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2018
Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting Antigen-presenting cell Maturation and Th17 cell Activation
Author Affiliations & Notes
  • Man Yu
    Ophthalmology, Schepens Eye Research Institute/Massachusetts Ear and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
    Ophthalmology, Sichuan Academy of Medical Sciences&Sichuan Provincial People's Hospital, Chengdu, Sichuan, China
  • Yihe Chen
    Ophthalmology, Schepens Eye Research Institute/Massachusetts Ear and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Sang-Mok Lee
    Ophthalmology, Schepens Eye Research Institute/Massachusetts Ear and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Takeshi Nakao
    Ophthalmology, Schepens Eye Research Institute/Massachusetts Ear and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Reza Dana
    Ophthalmology, Schepens Eye Research Institute/Massachusetts Ear and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, United States
  • Footnotes
    Commercial Relationships   Man Yu, None; Yihe Chen, None; Sang-Mok Lee, None; Takeshi Nakao, None; Reza Dana, None
  • Footnotes
    Support  NIH R01 EY20889
Investigative Ophthalmology & Visual Science July 2018, Vol.59, 4957. doi:
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      Man Yu, Yihe Chen, Sang-Mok Lee, Takeshi Nakao, Reza Dana; Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting Antigen-presenting cell Maturation and Th17 cell Activation. Invest. Ophthalmol. Vis. Sci. 2018;59(9):4957.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Substance P (SP) levels have been shown to increase in the early induction phase of dry eye disease (DED). However, the contribution of SP to the immunopathogenesis of DED has not been fully elucidated. In this study, we aimed to investigate the effect of topical blockade of SP receptor, Neurokinin-1 (NK1R), on disease severity, antigen presenting cell maturation and Th17 cell activation in a mouse model of DED.

Methods : DED was induced in female C57BL/6 mice by placing them in the controlled environment chamber for 14 days. Mice were assigned to one of four groups (n=5 each): 1μg/μl of NK1R antagonists CP-99,994 or L-733,060 was administered topically three times per day from day 4 to day 14 after DED induction, and PBS-treated mice served as controls. Corneal fluorescein staining (CFS) was performed to evaluate disease severity. Corneas, conjunctivae and draining lymph nodes (dLNs) of different groups were harvested at day 14. Frequencies of MHC-IIhiCD11b+cells in corneas and dLNs, and Th17 cells in conjunctivae and dLNs were evaluated using flow cytometry. mRNA expression of IL-17 in conjunctivae was measured using RT-PCR.

Results : Compared with PBS-treated controls, topical application of either NK1R antagonists CP-99,994 or L-733,060 significantly decreased CFS scores of DED mice at day 7, 10 and 14 (p<0.05). Both CP-99,994 and L-733,060 decreased the frequencies of MHC-IIhi CD11b+cells in the cornea and dLNs (p=0.005 and p=0.001, respectively), as well as the level of MHC-II expression by CD11b+ cells in dLNs (p=0.003 and p=0.02, respectively) compared to PBS-treated controls. These changes were accompanied by a significant decrease in frequencies of Th17 cells in conjunctivae (p= 0.02 for CP-99,994, and p= 0.01 for L-733,060) and dLNs (p= 0.02 for CP-99,994, and p=0.01 for L-733,060). mRNA expression levels of inflammatory cytokine IL-17 were significantly reduced in conjunctivae of mice treated with either CP-99,994 or L-733,060 compared to the control group (p=0.001).

Conclusions : These results demonstrate that topical blockade of SP receptor (NK1R) ameliorates dry eye disease by inhibiting antigen presenting cell maturation and Th17 cell activation.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.

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