Identification, signaling, and functions of LTB4 receptors

Leukotriene B₄ (LTB₄), a lipid mediator produced from arachidonic acid, is a chemoattractant for inflammatory leukocytes. We identified two receptors for LTB₄, the high-affinity receptor BLT1 and the low-affinity receptor BLT2. BLT1 is expressed in various subsets of leukocytes, and analyses of BLT1-deficient mice revealed that the LTB₄/BLT1 axis enhances leukocyte recruitment to infected sites, and is involved in the elimination of pathogens. Hyperactivation of the LTB₄/BLT1 axis induces acute and chronic inflammation, resulting in various inflammatory diseases. BLT2 was originally identified as a low-affinity receptor for LTB₄, and we later identified 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) as a high-affinity ligand for BLT2. BLT2 is highly expressed in epithelial cells in various tissues including intestine and skin. Large quantities of 12-HHT are produced by activated platelets during skin injury, and activation of BLT2 on epidermal keratinocytes accelerates skin wound healing by enhancing cell migration. BLT2 signaling also enhances cell-cell junctions, protectes against transepidermal water loss, and preventes entry of environmental substances into the body.