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Becca A Flitter, Nicole M. Rossi, Arnav Modi, Christine Cheung, Rose Li, Karsten Gronert; 5 Lipoxygenase Mediates Sex-Specific Protective Responses in Dry Eye Disease. Invest. Ophthalmol. Vis. Sci. 2019;60(9):6725. doi: https://doi.org/.
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The majority of Dry Eye Disease (DED) patients are female, however, the immune mediated mechanisms for this sex-specific difference remain undefined. Neutrophils (PMNs) are recognized as cellular mediators that regulate adaptive immune responses and wound healing. PMNs generate the lipid mediator lipoxin A4 (LXA4) which modulates innate and adaptive immune responses. LXA4 production depends on the enzyme 5 lipoxygenase (5-LOX), yet tissue stimuli that promote PMNs to generate this protective lipid are unknown. Previously, we showed PMNs are present in healthy lacrimal glands (LG) and regulate deleterious T cell responses in DED. Here we investigate the impact of 5-LOX on sex-specific immune responses in the LG during DED.
Male and female C57BL/6 (WT) or 5-LOX KO (Alox5-/-) mice were subjected to desiccating stress to induce DED. After 10 days of DED, some mice were returned to normal housing for 10 days to assess DED recovery. Corneal disease severity was determined by fluorescein staining. LG homogenates were analyzed using 23 Bio-plex for cytokines and chemokines and immune cell frequencies by flow cytometry and immunofluorescence imaging. Lastly, LC/MS/MS was used to profile and quantify lipid mediator generation in LGs.
To determine if initial LG immune responses were important for sex specific disease severity, we examined WT males and females after 3 days of desiccating stress. WT males had significantly higher LXA4 in the LG compared to WT females, which corresponded with elevated PMN frequencies. Sex specific chemokine profiles were detected at day 3, WT males had higher CXCL1 whereas WT females had elevated MCP-1, CCL3 and CCL4. These chemokine signatures were reduced in Alox5-/- males and females. After 10 days of DED, WT and Alox5-/- females had worse disease and elevated IL-1α, IFNγ and G-CSF than WT and Alox5-/- males. As LXA4 modulates T cell function, we investigated if 5-LOX was essential for restoring LG homeostasis. After DED and a recovery period, DED was reduced in WT females, while Alox5-/- females continued to have severe DED.
DED induces sex-specific LXA4 production, PMN frequencies, cytokine and chemokine profiles in the LG. 5-LOX is a key sex-specific regulator of healthy immune responses in the LG and is critical for restoring homeostasis in females. A better understanding of tissue stimuli that drive PMN LXA4 generation may provide new therapies for DED.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.
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