Chronic nonhealing wounds such as diabetic ulcers are a major problem associated with human disease. In this issue, Liu et al. offer new hope for tackling nonhealing wounds by defining a novel role for the leukotriene B4 receptor type 2 (BLT2) and its ligand 12-hydroxyheptadecatrienoic acid (12-HHT) in wound healing. They also show that high-dose aspirin delays wound healing by reducing the levels of 12-HHT.

Endogenously produced lipid autacoids are locally acting, small molecule mediators that regulate diverse processes such as inflammation, asthma, colitis, tissue regeneration, and cancer. Unlike prostaglandins and leukotrienes, the biological roles of 12-HHT and its receptor BLT2 have been poorly characterized. 12-HHT, a downstream lipid metabolite of cyclooxygenase 1 (COX1) and COX2, was previously assumed to be an inert by-product of arachidonic acid metabolism until its recent identification as an endogenous high-affinity ligand for BLT2 by this group. It is known that high-dose aspirin, the most commonly used nonsteroidal anti-inflammatory drug (NSAID) targeting the COX pathway, delays wound healing but the mechanism by which this delay occurs has been poorly characterized. Most of aspirin’s pharmacological effect has been attributed to its blockage of thromboxanes and prostaglandin production. However, low-dose aspirin has been found to trigger production of beneficial, anti-inflammatory, and pro-resolution mediators by COX2, the aspirin-triggered resolvins, and lipoxins, thus alleviating inflammation via stimulating endogenous resolution mechanisms. It is possible that high-dose aspirin inhibits a range of anti-inflammatory lipid metabolites, some yet unidentified, which may account for some of its side effects.

Now, in a series of elegant experiments using genetic and pharmacological manipulation of endogenous 12-HHT levels, Liu et al. demonstrate for the first time that 12-HHT promotes wound healing by accelerating keratinocyte migration via the BLT2 receptor, resulting in enhanced re-epithelialization in the skin. The 12-HHT/BLT2 axis induces keratinocyte migration and wound closure through NF-κB dependent up-regulation of TNF and matrix metalloproteinase 9 (MMP9). Remarkably, a synthetic BLT2 agonist accelerated wound closure in a mouse diabetes model. These pioneering studies by Liu et al. provide the first mechanistic insight into the deleterious effect of high-dose aspirin on wound healing.

These results suggest a direct anti-inflammatory role of BLT2 that is distinct from the proinflammatory roles of BLT1. Liu et al. offer a mechanistic rationale for evaluating BLT agonists as novel therapeutics to accelerate wound healing. Based on these exciting results, the largely unexplored lipid autacoid 12-HHT/BLT2 axis should now be evaluated as potential therapeutic targets in other inflammation-associated diseases such as cancer, atherosclerosis, and sepsis.

et al
J. Exp. Med.