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Helen P Makarenkova, Valery I Shestopalov, Mohamad Moghadam, Liana Basova; Analysis of inflammasome formation in the lacrimal gland during acute and chronic inflammation. Invest. Ophthalmol. Vis. Sci. 2018;59(9):2577.
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© ARVO (1962-2015); The Authors (2016-present)
Aqueous Deficiency Dry Eye disease (ADDE) is a multifactorial disorder of the tear film and ocular surface that primarily targets the lacrimal glands (LG). While inflammation plays a critical role in many cases of ADDE, the role of inflammasomes in acute and chronic phases of LG inflammation in vivo remains unknown.
Acute (IL1α and lipopolysaccharide (LPS)) and chronic thrombospondin null (TSP-1-/-) mouse models were used to study LG inflammation. Inflammasome activation in vivo was studied using novel transgenic mice that ectopically express the fluorescent citrine bioindicator protein, fused to the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC)(Tzeng et al., 2016). In addition, the expression profiles of inflammasome sensors NLRP3, NLRC4, NLRP6, NRLP12, Casp1, Casp4 (also known as Casp11) and cytokine production was studied by qRT PCR and immunohistochemistry.
Numerous large and small size specks were detected in the LG secretory acinar and myoepithelial cells one day after LG injury. This suggests that LG epithelial cells (acinar and MEC) are the primary responders to inflammation. Only sparse small specks were detectable in control and naïve LGs. Numerous large size speck formation was found only in chronically inflamed LGs of TSP1-/- mice. Inflammasome activation in acinar and MECs was associated with Casp1and 4(11) increase, production of IL-1β, IL-6, IL-18 and modulation of NLRP proteins, whereas constitutive levels of fibroblast growth factor 10 (FGF10) known to be vital for stem cell maintenance and LG regeneration was strongly reduced. In addition, expression of Panx1, P2X4 and P2X7 receptors, implicated in inflammasome activation, was upregulated.
In this study we have shown that ASC-citrine is a reliable biomarker of LG inflammation, which allows detection of responding cell types in real time in vivo. We also found early and robust inflammasome activation and upregulation of inflammasome sensors primarily in the LG acinar and MECs cells that makes them the primary target of acute and chronic inflammation.
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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