Essential fatty acids (EFAs)-cis-linoleic acid (LA,18:2 n-6) and alpha-linolenic acid (ALA, 18:3 n-3)-are widely distributed in the diet and serve as precursors of several bioactive lipid molecules, including prostaglandins (PGs), leukotrienes (LTs), and thromboxanes (TXs), which exert predominantly pro-inflammatory effects. Both LA and ALA undergo enzymatic conversion by desaturases (Δ6 and Δ5) and elongases, giving rise to gamma-linolenic acid (GLA, 18:3 n-6), dihomo-GLA (DGLA, 20:3 n-6), and arachidonic acid (AA, 20:4 n-6) from LA and to eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3) from ALA. From AA, PGs and TXs of the 2-series and LTs of the 4-series are produced, whereas EPA gives rise to PGs and TXs of the 3-series and LTs of the 5-series, through the action of cyclooxygenase-2 (COX-2). Although all of these metabolites are pro-inflammatory, those derived from EPA are less so than those formed from AA. Importantly, AA is also the precursor of lipoxin A4 (LXA4), a potent anti-inflammatory molecule. Similarly, resolvins of the E-series are derived from EPA, while resolvins of the D-series, protectins, and maresins are generated from DHA; all of these have anti-inflammatory activity. Notably, DHA does not produce PGs, TXs, or LTs. Thus, AA, EPA, and DHA serve as precursors of both pro-inflammatory (except DHA) and anti-inflammatory eicosanoids (Figure 1). The balance between these metabolites is expected to determine the overall outcome of the inflammatory response.
LXA4, resolvins, protectins, and maresins exert their anti-inflammatory effects primarily by inhibiting the production of pro-inflammatory cytokines such as interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and macrophage migration inhibitory factor (MIF), while enhancing the formation of anti-inflammatory cytokines. They also suppress the expression of NF-κB, COX-2, and the cGAS-STING pathway. Interestingly, the fatty acids GLA, DGLA, AA, EPA, and DHA themselves also demonstrate anti-inflammatory activity to some extent, by reducing the expression of IL-6, TNF-α, NF-κB, and COX-2 (Figure 2). The significance of AA, EPA, and DHA lies in their role as integral components of the phospholipid fraction of all cell membranes. Various internal and external stimuli activate phospholipase A2 (PLA2), which in turn promotes the release of AA, EPA, and DHA-the precursors of multiple eicosanoids.
There is evidence that IL-6, TNF-α, MIF, PGs, LTs, and TXs are released by M1 macrophages, dendritic cells, NK cells, T cells, and other immunocytes, whereas M2 macrophages produce IL-10, LXA4, resolvins, protectins, and maresins. Pro-inflammatory cytokines activate PLA2, thereby promoting the formation of PGs, LTs, and TXs, while anti-inflammatory cytokines enhance the generation and release of LXA4, resolvins, protectins, and maresins. This process is reciprocal; for example, PGE2 stimulates the release of IL-6 and TNF-α, whereas LXA4 induces the production of the anti-inflammatory cytokine IL-10. This dynamic crosstalk among immunocytes, cytokines, and eicosanoids regulates the inflammatory process and immune response-both innate and adaptive-while promoting the resolution of inflammation, facilitating wound healing, and restoring homeostasis. Several aspects of the complex interactions among EFAs, eicosanoids, LXA4/resolvins/protectins/maresins, cytokines, macrophages, and T cells in the regulation of inflammation and immunity (Figure 2) have been discussed in detail elsewhere.1-5 Collectively, these studies suggest that bioactive lipids may play a significant role in the pathobiology of uveitis.1-6
Lipoxins appear to regulate both innate and adaptive immune systems-including neutrophils, macrophages, and T and B cells-through their ability to modulate NF-κB, activator protein-1, nerve growth factor-regulated factor 1A binding protein 1, and peroxisome proliferator-activated receptor γ, thereby controlling the expression of numerous inflammatory genes.1-6 In an animal model of lipopolysaccharide (LPS)-induced posterior uveitis, characterized by retinal neuroinflammation due to activation of resident microglia (astrocytes and Müller glia), lipoxins were shown to reduce retinal inflammation by inhibiting CXCL9 (MIG) and CXCL10 (IP-10).7 LXA4 also decreased expression of IL-1β, TNF-α, Notch-1, Hes1, iNOS, and CD32-markers of the M1 microglia phenotype-while upregulating Hes5, Arg-1, and CD206, which are associated with the M2 phenotype. These findings suggest that LXA4 regulates microglial polarization after injury via the Notch signaling pathway.8 Beyond the eye, LXA4 exerts neuroprotective effects within the central nervous system, including in uveitis.9 In another study, reduced LXA4 levels were observed in patients with posterior segment uveitis, while LXA4-deficient mice exhibited amplified T-cell effector function, migration, and glycolytic activity that correlated with severe pathology. In contrast, LXA4 treatment attenuated disease severity.10 Furthermore, LXA4 was shown to regulate natural killer cell and type 2 innate lymphoid cell activation.11 Importantly, LXA4 dampens T effector cell responses in autoimmune uveitis. Topical application of LXA4 (10 ng/eye) inhibited LPS-induced IL-1β, TNF-α, PGE2, and the expression of COX-2, VEGF, NF-κB, and c-JUN as effectively as corticosteroids (200 μg/eye). This suggests that LXA4 may be a promising therapeutic candidate for ocular inflammatory conditions, including uveitis.12,13 Similar anti-inflammatory effects have also been reported for resolvin D1.14,15
Taken together, these findings highlight that LXA4, along with resolvins, protectins, and maresins, play a critical role in the pathobiology of uveitis and may serve as an endogenous cytoprotective, neuroprotective, and anti-inflammatory mediator.
Further studies are clearly needed. It would be valuable to measure tear fluid, vitreous, and plasma levels of LXA4, resolvins, protectins, and maresins and to correlate these concentrations with IL-6, TNF-α, MIF, and the expression of NF-κB, desaturases, COX-2, and lipoxygenases. Definitive clinical studies are required to evaluate the effects of intravitreal and topical administration of LXA4, resolvins, protectins, and maresins in order to determine which of these endogenous anti-inflammatory mediators are most effective. Should topical application prove beneficial, it could mark a new era in the prevention and management of uveitis and other inflammatory eye diseases.
Acknowledgements: Dr. (Prof.) UND was in receipt of visiting fellowship from TUBİTAK of Türkiye during the tenue of this study.
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