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Vanessa Laura Jennifer DELCROIX, Amrita Srivastava, Liana Basova, Andrew Wong, Takeshi Umazume, Valery I Shestopalov, Helen P Makarenkova; Myoepithelial Cells Are Necessary For Lacrimal Gland Function. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2619.
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© ARVO (1962-2015); The Authors (2016-present)
Aqueous deficiency dry eye (ADDE) is characterized by a lack or altered composition of tear secretion from the lacrimal gland (LG). Previously we have shown that severe inflammation affects acini contraction in the LGs of mouse models for ADDE. We hypothesize that alteration of MECs by inflammation is responsible for the dysfunction of acinar cells and LG.
10-26 month old C57BL/6J mice were used to study LG aging. Thrombospondin null (TSP-1-/-) mice were used as models of chronic inflammation. In addition, R26CAG-ASC-citrine mice expressing the fluorescent adaptor apoptosis-associated speck-like protein (ASC) were used to study acute LG injury after interleukin 1 alpha (IL-1α) injection. A MEC function was analyzed by the oxytocin-induced LG acini contraction. The LG inflammation/function was studied by immunological techniques and measurement of basal tears (using the phenol red thread test). To investigate the role of MECs in LG function, MECs were depleted using the αSMACreErt2:R26iDTA mouse, in which diphtheria toxin fragment A (DTA) is produced in cells expressing α-SMA upon TM administration.
Our previous studies suggest that maintenance of acini polarity and contraction is essential for sufficient tear secretion. Here we show that aging and inflammation impaired MEC contraction and expression pattern of aquaporin-5, suggesting that inflammation also affects acinar polarity. Analysis of inflammasome formation after LG acute injury showed that inflammasomes were formed in MECs, as early as 6 hours after IL-1α injection, and only subsequently in acinar cells, thus suggesting that MECs are the primary target of inflammation. Inflammasome activation was associated with production of IL-1β. To confirm the specific role for MECs in LG dysfunction, we depleted MECs in vivo using the αSMACreErt2:R26iDTA mouse model. Depletion of MECs lead to complete LG dysfunction and mimicked ADDE, resulting in the alteration of acinar polarity, the loss of oxytocin-induced contraction and reduced basal tear release.
Our results support the concept that MECs control acini polarity and contraction and therefore, the secretory function of acinar cells. Moreover, our study suggests that loss of MEC functions is an early event in the development of ADDE. Therapeutic strategies reducing the inflammation and/or restoring MEC function are likely to be relevant for the treatment of ADDE.
This is a 2020 ARVO Annual Meeting abstract.
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