Leukotriene B(4) receptors as therapeutic targets for ophthalmic diseases.

Leukotriene B (LTB) is an inflammatory lipid mediator produced from arachidonic acid by multiple reactions catalyzed by two enzymes 5-lipoxygenase (5-LOX) and LTA hydrolase (LTAH). The two receptors for LTB have been identified: a high-affinity receptor, BLT1, and a low-affinity receptor, BLT2. Our group identified 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) as a high-affinity BLT2 ligand. Numerous studies have revealed critical roles for LTB and its receptors in various systemic diseases. Recently, we also reported the roles of LTB, BLT1 and BLT2 in the murine ophthalmic disease models of mice including cornea wound, allergic conjunctivitis, and age-related macular degeneration. Moreover, other groups revealed the evidence of the ocular function of LTB. In the present review, we introduce the roles of LTB and its receptors both in ophthalmic diseases and systemic inflammatory diseases. LTB and its receptors are putative novel therapeutic targets for systemic and ophthalmic diseases.

Hirakata T ，Matsuda A ，Yokomizo T 《-》

A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung.

Leukotriene B4 (LTB4), a potent lipid mediator of inflammation derived from arachidonic acid through the action of 5-lipoxygenase, has been implicated in the pathophysiology of several inflammatory diseases, including asthma and chronic obstructive pulmonary disease. A high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles. A cyclooxygenase metabolite, 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT), is an endogenous ligand for BLT2, a low-affinity LTB4 receptor. The recent study indicated that BLT2 has a protective role in allergic airway inflammation, suggesting different functions between BLT1 and BLT2 in the pathogenesis of asthma. Selective BLT1 antagonists may have a potential therapeutic application in patients with asthma, and BLT2 may represent a novel therapeutic target for lung diseases.

Watanabe M ，Machida K ，Inoue H 《-》

Identification, signaling, and functions of LTB(4) receptors.

Leukotriene B (LTB), a lipid mediator produced from arachidonic acid, is a chemoattractant for inflammatory leukocytes. We identified two receptors for LTB, 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 LTB/BLT1 axis enhances leukocyte recruitment to infected sites, and is involved in the elimination of pathogens. Hyperactivation of the LTB/BLT1 axis induces acute and chronic inflammation, resulting in various inflammatory diseases. BLT2 was originally identified as a low-affinity receptor for LTB, 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.

Saeki K ，Yokomizo T 《-》

Two distinct leukotriene B4 receptors, BLT1 and BLT2.

Leukotriene B4 (LTB4) is a potent inflammatory mediator derived from arachidonic acid. Two G protein-coupled receptors for LTB4 have been identified: a high-affinity receptor, BLT1, and a low-affinity receptor, BLT2. Both receptors mainly couple to pertussis toxin-sensitive Gi-like G proteins and induce cell migration. 12(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid (12-HHT) was identified to bind BLT2 with higher affinity than LTB4. Expression of BLT1 was confirmed in type 1 helper T cells, type 2 helper T cells, type 17 helper T cells, effector CD8(+) T cells, dendritic cells and osteoclasts in addition to granulocytes, eosinophils and macrophages, and BLT1-deficient mice showed greatly reduced phenotypes in models of various inflammatory diseases, such as peritonitis, bronchial asthma, rheumatoid arthritis, atherosclerosis and osteoporosis. In mice, BLT2 expression is restricted to intestinal epithelial cells and epidermal keratinocytes. BLT2-deficient mice showed enhanced colitis after administration of dextran sulfate, possibly due to reduced intestinal barrier function. An aspirin-dependent reduction in 12-HHT production was responsible for delayed skin wound healing, showing that the 12-HHT/BLT2 axis also plays an important role in skin biology. BLT1 and BLT2 are therefore potential targets for the development of novel drugs.

Yokomizo T 《-》

Macrophage LTB(4) drives efficient phagocytosis of Borrelia burgdorferi via BLT1 or BLT2.

Unresolved experimental Lyme arthritis in C3H 5-lipoxygenase (5-LOX) mice is associated with impaired macrophage phagocytosis of In the present study, we further investigated the effects of the 5-LOX metabolite, leukotriene (LT)B on phagocytosis of Bone marrow-derived macrophages (BMDMs) from 5-LOX mice were defective in the uptake and killing of from the earliest stages of spirochete internalization. BMDMs from mice deficient for the LTB high-affinity receptor (BLT1) were also unable to efficiently phagocytose Addition of exogenous LTB augmented the phagocytic capability of BMDMs from both 5-LOX and BLT1 mice, suggesting that the low-affinity LTB receptor, BLT2, might be involved. Blocking BLT2 activity with the specific antagonist, LY255283, inhibited phagocytosis in LTB-stimulated BLT1 BMDMs, demonstrating a role for BLT2. However, the lack of a phagocytic defect in BLT2 BMDMs suggested that this was a compensatory effect. In contrast, 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid, a natural BLT2-specific high-affinity ligand, and resolvin E1, a BLT1 agonist, were both unable to boost phagocytosis in BMDMs from either 5-LOX or BLT1 mice, suggesting a specific role for LTB in mediating phagocytosis in murine macrophages. This study demonstrates that LTB promotes macrophage phagocytosis of bacteria via BLT1, and that BLT2 can fulfill this role in the absence of BLT1.

Zhang Y ，Olson RM ，Brown CR 《-》