Dietary DHA amplifies LXA4 circuits in tissues and lymph node PMN and is protective in immune-driven dry eye disease

Recently identified regulatory PMN control immune-driven dry eye disease (DED) in females by producing the arachidonic acid (omega-6)-derived specialized pro-resolving mediator (SPM), LXA(4), in lymph nodes. Dietary omega-3 docosahexaenoic acid (DHA) is protective in DED but mechanisms of action remain elusive. DHA is converted to omega-3 SPMs by PMN via the same lipoxygenases (LOX) that generate LXA(4). We investigated if dietary DHA amplifies SPM formation and affects T effector cell function and/or regulatory PMN in DED. DED was induced in mice on a DHA-enriched or omega-3-deficient diet. DHA deficiency amplified DED with marked sex-specific differences. Dietary DHA protection against dry eye disease correlated with increased PMN levels in lymph nodes, ocular tissues, and unexpectedly, selective amplification of LXA(4) tissue levels. Dietary DHA increased 12/15-LOX and decreased 5-LOX expression in lymph nodes and isolated lymph node PMN, which correlated with amplified LXA(4) formation. Acute DHA treatment rescued DHA-deficient females from exaggerated DED by amplifying lymph node LXA(4) formation, increasing T-reg and decreasing T(H)1 and T(H)17 effector cells. Our results identify DHA regulation of LXA(4) producing PMN in ocular tissues and lymph nodes in health and immune disease as novel mechanism and determinant for T-cell responses to routine ocular injury or stress signals.