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.

Combined Therapy Using Human Corneal Stromal Stem Cells and Quiescent Keratocytes to Prevent Corneal Scarring after Injury

“…This could be due to the reduced levels of COX product 12(S)-hydroxyheptaseca-5Z,8E,10E-trienoic acid (12-HHT) after COX suppression [44]. The endogenous ligand for leukotriene B4 receptor 2 is 12-HHT, which is important for tissue homeostasis, including corneal tissues [45]. Hence, NSAID eye drops that inhibit the production of 12-HHT delays corneal wound healing [43].…”

Role of Leukotriene B4 Receptor-2 in Mast Cells in Allergic Airway Inflammation

“…LTB 4 is one of the most potent known chemoattractants, acting primarily on neutrophils, eosinophils, T cells, and mast cells [5,16,17,18]. LTB 4 has been widely implicated in the pathogenesis of several inflammatory diseases, including asthma, psoriasis, rheumatoid arthritis, and inflammatory bowel disease [19]. LTB 4 also exerts its biological functions via two types of G protein-coupled receptors (GPCRs): BLT1, which is predominantly expressed in peripheral blood leukocytes, and BLT2, which is expressed ubiquitously [19].…”

“…LTB 4 has been widely implicated in the pathogenesis of several inflammatory diseases, including asthma, psoriasis, rheumatoid arthritis, and inflammatory bowel disease [19]. LTB 4 also exerts its biological functions via two types of G protein-coupled receptors (GPCRs): BLT1, which is predominantly expressed in peripheral blood leukocytes, and BLT2, which is expressed ubiquitously [19]. Previous studies have reported that both BLT1 and BLT2 are expressed in human and murine mast cells, and that both receptors contribute to the chemotactic migration of mast cells toward LTB 4 [18,19].…”

“…LTB 4 also exerts its biological functions via two types of G protein-coupled receptors (GPCRs): BLT1, which is predominantly expressed in peripheral blood leukocytes, and BLT2, which is expressed ubiquitously [19]. Previous studies have reported that both BLT1 and BLT2 are expressed in human and murine mast cells, and that both receptors contribute to the chemotactic migration of mast cells toward LTB 4 [18,19]. LTB 4 activates the BLT1 and BLT2, whereas additional lipid mediators (12( S )-hydroxyeicosatetraenoic acid (HETE) and 12-hydroxyheptadecatrienoic acid (12-HHT)) are also agonists to the BLT2 [18,19].…”

“…Previous studies have reported that both BLT1 and BLT2 are expressed in human and murine mast cells, and that both receptors contribute to the chemotactic migration of mast cells toward LTB 4 [18,19]. LTB 4 activates the BLT1 and BLT2, whereas additional lipid mediators (12( S )-hydroxyeicosatetraenoic acid (HETE) and 12-hydroxyheptadecatrienoic acid (12-HHT)) are also agonists to the BLT2 [18,19]. Previous studies have suggested that BLT2 plays a mediatory role in the pathogenesis of the allergic airway inflammation in asthma through its action in mast cells [20,21,22,23].…”