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 (ω-6)-derived specialized pro-resolving mediator (SPM), LXA₄, in lymph nodes. Dietary ω-3 docosahexaenoic acid (DHA) is protective in DED but mechanisms of action remain elusive. DHA is converted to ω-3 SPMs by PMN via the same lipoxygenases (LOX) that generate LXA₄. 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 ω-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 LXA₄ 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 LXA₄ formation. Acute DHA treatment rescued DHA-deficient females from exaggerated DED by amplifying lymph node LXA₄ formation, increasing T_reg and decreasing T_H1 and T_H17 effector cells. Our results identify DHA regulation of LXA₄ 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.