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

Abstract

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), LXA, 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 LXA. 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 LXA 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 formation. Acute DHA treatment rescued DHA-deficient females from exaggerated DED by amplifying lymph node LXA formation, increasing T and decreasing T1 and T17 effector cells. Our results identify DHA regulation of LXA 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.

Mouse strains and sexual divergence in corneal innervation and nerve regeneration

“…One possibility is that the higher gene activation of alox15 in the TG of the female mouse allows the synthesis of docosanoids to enhance the nerve regeneration. This suggestion is supported by previous studies that showed the benefit of lipoxin A 4 , a 15-LOX-related derivative of arachidonic acid for female mice in the immune-driven dry eye model (43, 44). Moreover, alox15 was shown to be a shared activated gene between the 3 mouse strains.…”

Fair‐Weather Friends: Evidence of Lipoxin Dysregulation in Neurodegeneration

“…Consequently, restoration or supplementation of LX signaling may also present promising therapeutic potential, as they induce a proresolving effect in models of neuroinflammation, while also exerting direct neuroprotective activity. Recent interesting evidence suggests that dietary supplementation of omega‐3 PUFA can sustain the levels of SPMs in AD patients and amplifies LXA 4 levels in several tissues in mice …”

“…However, changes in AA or linoleic acid dietary intake can alter formation of other pro‐inflammatory metabolites, such as leukotrienes and prostaglandins . We have also recently shown that dietary changes in omega‐6 and omega‐3 PUFA intake can alter enzymatic LX production in the contexts of parenteral nutrition and ocular inflammation …”

Eicosanoid and Specialized Proresolving Mediator Regulation of Lymphoid Cells

“…Recent studies have uncovered the important roles of endogenous and tissue resident LXA 4 circuits on T cell function. The immune regulatory function of LXA 4 on cells was investigated in vivo in an immune-driven dry eye model, where neutrophil-derived LXA 4 was a critical resident signal to control pathogenic T helper cell type 1 (Th1) and T helper cell type 17 (Th17) effector cells and increased the number of T regulatory cells (Tregs) in the eye draining lymph nodes [11,12]. More importantly, sex-specific regulation of the LXA 4 circuit in resident lymph nodes was identified as a key factor that drives femalespecific immune-driven dry eye disease.…”

“…Recent reports have demonstrated that lipoxins are not only formed during inflammation and the resolution phase of inflammation, but that they are also part of normal signaling in healthy tissues and actively regulate homeostasis and the threshold for activation of immune responses in the cornea, lymph nodes, lacrimal glands and retina [11,12,19,20]. Regulation and therapeutic amplification of this homeostatic SPM circuit in health and diseases is the focus of several NIH-funded projects.…”