Biological functions of 12(S)-hydroxyheptadecatrienoic acid as a ligand of leukotriene B4 receptor 2

Abstract

Although 12(S)-hydroxyheptadecatrienoic acid (12-HHT) is an abundant fatty acid, it is long considered a byproduct of thromboxane A₂ production. We identified a leukotriene B₄ receptor 2 (BLT2)-specific agonistic activity in lipid extracts from rat small intestine, and mass spectrometric analysis of partially purified lipids containing BLT2 agonistic activity revealed that 12-HHT is an endogenous ligand of BLT2. In a dextran sulfate sodium (DSS)-induced inflammatory colitis model, BLT2-deficient mice exhibited enhanced intestinal inflammation, possibly due to impaired epithelial barrier function. In a skin wound healing model, BLT2-deficient mice exhibited delayed wound healing via dampened keratinocyte migration. BLT2 also accelerates corneal wound healing, and eye drops containing a non-steroidal anti-inflammatory drug (NSAID) inhibit the production of 12-HHT, resulting in delayed corneal wound healing. Furthermore, BLT2 is expressed in pulmonary epithelial type II cells and vascular endothelial cells in the mouse lung, and BLT2-deficient mice are more susceptible to lung damage by pneumolysin. In this review, we summarize the identification and characterization of 12-HHT as a ligand for BLT2 and discuss recent research on the physiological and pathophysiological roles of the 12-HHT-BLT2 axis. Some side effects of NSAIDs such as delayed wound healing may be caused by reduced 12-HHT production rather than diminished production of prostaglandins.