In the immune-privileged cornea, epithelial wounds heal rapidly with almost no scarring and, unlike in most other tissues, acute inflammation in the absence of infection is beneficial to healing. Molecular mechanisms, which account for this striking property, remain to be clearly defined, but they likely include autacoids that control leukocyte activation. Two prominent enzymes, 12/15-lipoxygenase (LOX), which generates antiinflammatory lipid autacoids, and heme-oxygenase (HO), which generates antioxidants and carbon monoxide, are highly expressed in human and mouse corneas. LXA₄, an endogenous 12/15-LOX product, proved to be a potent inhibitor of exacerbated inflammation and significantly increased re-epithelialization in corneal wounds. In vivo deletion of 12/15-LOX correlated with exacerbated inflammation and impaired wound healing in 12/15-LOX^-/- mice, a phenotype that was rescued by treatment with LXA₄. More importantly, 12/15-LOX^-/- mice demonstrated impaired induction of HO-1 in both acute and exacerbated inflammation. Topical LXA₄ restored HO-1 expression in 12/15-LOX^-/- mice and amplified HO-1 gene expression in human corneal epithelial cells. HO-2^-/- mice, which fail to induce HO-1, also demonstrated exacerbated inflammation in response to injury, a phenotype that, notably, correlated with a 50% reduction in endogenous LXA₄ formation. Collectively, results demonstrate a critical role for LXA₄ in inflammatory/reparative responses and provide the first evidence that 12/15-LOX and HO systems function in concert to control inflammation.--Biteman, B., Hassan, I. R., Walker, E., Leedom, A. J., Dunn, M., Seta, F., Laniado-Schwartzman, M., Gronert, K. Interdependence of lipoxin A₄ and heme-oxygenase in counter-regulating inflammation during corneal wound healing.