Immune Homeostasis and Aging Lipid Mediator Circuits

Abstract

Purpose : Aging is a primary risk factor for dysregulated routine ocular surface immune responses, which can lead to autoimmune diseases, such as Dry Eye. Our knowledge of how aging impacts the delicate regulation of healthy and essential immune responses is very limited. Lipid mediators, such as the lipoxin circuit, have emerged as important resident pathways that regulate leukocyte and T cell functions and homeostasis in the retina and ocular surface. The goal of this study was to characterize how aging impacts lipid mediator circuits that regulate immune response in the ocular surface and eye.

Methods : Healthy 3-5 months old and 20-27 months old C57BL/6J male and female mice were housed under standard conditions. Eyes, lacrimal glands, draining lymph nodes, spleen, serum and bone marrow were collected for HPLC/LC/MS/MS-based lipidomic analysis. Gene expression of cyclooxygenase, lipoxygenase and lipoxin receptors in tissues was assessed by QPCR. Leukocytes were isolated from zymosan-induced peritonitis in young and aged mice to define leukocyte lipidome and expression of lipid mediator pathways and receptors.

Results : Lipidomic and QPCR analyses identified marked sex- and tissue-specific changes in aged mice. Specifically, 5-LOX and 15-LOX pathways, the lipoxin circuit and levels of prostaglandins were markedly altered in aged mice and showed sex-specific differences. Impaired 5-LOX activity and capacity to generate LXA₄ was a phenotype of leukocytes from aged mice.

Conclusions : Execution of healthy routine innate and adaptive immune responses depend on tight regulation of effector cells and return to immune homeostasis. Lipid mediator circuits, such as lipoxins and prostaglandins, are important local signals that control the threshold of activation, amplitude and duration of an immune response. Their formation and receptors are dynamically and tightly regulated. The data indicates that in healthy mice, aging alters the balance of lipid mediator circuits in leukocytes, lymph nodes, lacrimal glands and eye, which may set the stage to initiate dysregulated immune responses.

This is a 2021 ARVO Annual Meeting abstract.