Molecular Circuits of Resolution in the Eye

Abstract

Lipid autacoids have well-established key roles in physiology and pathophysiology. Eicosanoids derived from ω-6 arachidonic acid (AA) have long been recognized for their roles in cardiovascular and renal functions, and vascular tone, as well as regulating inflammatory and immune functions. It is now appreciated that AA is a substrate for generating lipid mediators with anti-inflammatory and proresolving properties, namely lipoxins (i.e., LXA4), which are an integral component for the successful execution of beneficial and essential acute inflammatory responses. In addition to AA, the ω-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also serve as substrates to generate potent and protective autacoids, such as resolvins and neuroprotectin (i.e., NPD1), respectively. These ω-3–derived signals may mediate the remarkable protective action of essential dietary ω-3 PUFAs. Formation and bioactivity of lipid mediators in the eye are relatively unexplored and of considerable interest, as the eye contains highly specialized tissues, including the transparent avascular and immune-privileged cornea, and the neuro-retina. A rapidly emerging field has identified key biosynthetic enzymes, receptors, and temporally defined endogenous formation of ω-3– and ω-6–derived protective lipid circuits in the eye. Protective endogenous roles of LXA4 and NPD1 have been established utilizing lipidomic analysis, knockout mice, and pharmacological, genetic, and dietary manipulation, providing compelling evidence that these intrinsic lipid autacoid circuits play essential roles in restraining inflammation, promoting wound healing, inhibiting pathological angiogenesis, and providing neuroprotection in the delicate visual axis.

UVB light regulates expression of antioxidants and inflammatory mediators in human corneal epithelial cells

“…UVB light was also found to increase cornea epithelial mRNA expression for the platelet and epithelial forms of 12-LOX, as well as 15-LOX-2, enzymes mediating the generation of anti-inflammatory and protective lipid mediators, including the lipoxins and the docosahexaenoic acid-derived protectins and resolvins [50, 51]. Recent studies have shown that lipid mediators such as lipoxin A 4 and the neuroprotectin D1 are generated in the cornea where they inhibit chemokine formation and promote corneal wound healing [52, 53].…”

The role of pro-resolving lipid mediators in ocular diseases

“…15-LOX-LXA 4 -ALX/FPR2 circuit has been identified as an important resident circuit that controls wound healing and immune responses at the ocular surface. Two 15-LOX enzymes ( ALOX15, ALOX15B ) have been identified in the human cornea [14, 15, 16] and the mouse homolog 12/15-LOX ( Alox15 ) is expressed in the corneal epithelium, retinal pigment epithelium (RPE) and lens [17, 18]. Knockdown of 15-LOX ( ALOX15 ) in the human RPE increased susceptibility to oxidative stress induced apoptosis [19].…”

Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea

“…This pathway is significantly amplified by the recruitment of specific polymorphonuclear (PMN) leukocytes and macrophage populations that carry 5‐LOX and/or 15‐LOX, which sets in motion a temporally defined counterregulatory program that drives inflammatory resolution. A striking feature in both mouse and human corneas is the high epithelial expression of 15‐LOX (21, 33) and the expression of the ALX receptors (29, 31, 33, 34). Acute and chronic inflammation selectively regulates expression of 15‐LOX and ALX receptors.…”