March 2012
Volume 53, Issue 14
Free
ARVO Annual Meeting Abstract  |   March 2012
Neurally-Mediated Signals from the Environment Activate an Immunohomeostatic Epithelial Cell - Immune Cell Network in the Lacrimal Gland
Author Affiliations & Notes
  • Austin K. Mircheff
    Dept of Physiology & Biophysics, Univ of Southern California, Los Angeles, California
  • Yanru Wang
    Dept of Physiology & Biophysics, Univ of Southern California, Los Angeles, California
  • Footnotes
    Commercial Relationships  Austin K. Mircheff, None; Yanru Wang, None
  • Footnotes
    Support  Unrestricted grant from Allergan.
Investigative Ophthalmology & Visual Science March 2012, Vol.53, 627. doi:
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      Austin K. Mircheff, Yanru Wang; Neurally-Mediated Signals from the Environment Activate an Immunohomeostatic Epithelial Cell - Immune Cell Network in the Lacrimal Gland. Invest. Ophthalmol. Vis. Sci. 2012;53(14):627.

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

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Abstract

Purpose: : Desiccating environments induce dry eye disease in murine models, but they appear to activate an immunohomeostatic response in the rabbit lacrimal gland (LG). The cellular basis of that response was investigated.

Methods: : LG were obtained from 6 virgin adult female rabbits that had experienced 23 desiccating T/H days during the previous month. mRNA abundances in extracts of individual LG and of laser capture microdissection samples were determined by real time RT-PCR. Isolated LG acinar cells (AC) were studied in a standard ex vivo model.

Results: : As reported previously, mean abundances of a cluster of transcripts, including mRNAs for the chemokines, CCL2 and CCL4, and the cytokines, IL-1α, IL-6, BAFF, and IL-10, increase according to exponential growth curves as rabbits are exposed to increasing numbers of desiccating T/H days. Abundances of the cluster transcripts varied between individual LG from the group that experienced 23 desiccating T/H days. Variations correlated strongly (0.877 < r < 0.957) and significantly (P < 0.0002) with variations in the abundance of IL-10 mRNA. CCL2 mRNA was localized primarily to acinar epithelial cells; CCL4 mRNA to both ductal epithelial cells and periductal / perivenular immune cell accumulations (pd/pvIC); and IL-1α, IL-6, BAFF, and IL-10 mRNAs primarily to pd/pvIC. The β-adrenergic agonist, isoproterenol (1 μM and 10 μM), increased the abundance of CCL2 mRNA up to 12-fold in ex vivo AC. At the same doses, the muscarinic cholinergic agonist, carbachol (CCh), had a slight inhibitory effect; it suppressed the response to isoproterenol but did not entirely prevent it. Neither agonist alone influenced CCL4 expression, but in combination they suppressed it by more than 50%.

Conclusions: : The findings suggest that the sympathetic and parasympathetic neurotransmitters which elicit LG fluid production also induce AC to up-regulate expression of CCL2; that increased levels of CCL2 recruit immune cells to the pd/pvIC; that the recruited immune cells express CCL4, IL-1α, IL-1β, IL-6, BAFF, and IL-10; and that pd/pvIC mediators enhance AC expression of CCL2. Plausibly, IL-1α, IL-6, and BAFF may support the immune cells’ survival and ongoing expression of IL-10 while IL-10 enforces immunoregulation. Exponential expansion of the response may result from the abilities of CCL2 and CCL4 to promote further recruitment of CCL4-expressing-, survival factor-expressing-, and IL-10-expressing cells. The normal balance between cholinergic and adrenergic neurotransmission may modulate this positive feedback, permitting it to proceed but preventing it from becoming pathological.

Keywords: lacrimal gland • immunomodulation/immunoregulation • cornea: tears/tear film/dry eye 
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