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 《-》

Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia.

Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by LTB4 and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). Although the high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles, the role of BLT2 in allergic inflammation has not been clarified. To study the function of BLT2 in development of asthma, we used mice model of ovalbumin (OVA)-induced allergic airway disease. The 12-HHT levels were elevated in bronchoalveolar lavage (BAL) fluids of OVA-sensitized/challenged wild-type mice. BLT2-deficient mice exhibited enhanced eosinophilia in BAL fluids after OVA exposure. Interleukin (IL)-13 levels in BAL fluids and IL-13-producing CD4(+) T cells in the lungs were elevated in BLT2-deficient mice compared to wild-type mice, whereas the levels of IL-4, IL-5, and interferon (IFN)-γ in BAL fluids and serum OVA-specific IgE were comparable. Transfection of BLT2-specific small interfering RNA enhanced IL-13 production in CD4(+) T cells in vitro. Expression of BLT2 mRNA in CD4(+) T cells was significantly reduced in patients with asthma compared to healthy control subjects. These findings indicate that BLT2 has a protective role in allergic airway inflammation and that diminished BLT2 expression in CD4(+) T cells may contribute to the pathophysiology of asthma.

Matsunaga Y ，Fukuyama S ，Okuno T ，Sasaki F ，Matsunobu T ，Asai Y ，Matsumoto K ，Saeki K ，Oike M ，Sadamura Y ，Machida K ，Nakanishi Y ，Kubo M ，Yokomizo T ，Inoue H ... -  《-》

Nonredundant roles for leukotriene B4 receptors BLT1 and BLT2 in inflammatory arthritis.

Lipid mediators derived from arachidonic acid through the cyclooxygenase and lipoxygenase pathways are known to be important mediators of inflammation. Studies in mouse models demonstrated an important role for the high-affinity leukotriene B(4) receptor BLT1 in arthritis, atherosclerosis, and asthma. BLT2, a low-affinity leukotriene B(4) receptor, was also shown to be a high-affinity receptor for cyclooxygenase-1 derived 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. However, its biochemical activities and physiological roles remain unknown. In this study, we developed mice deficient in BLT2 by targeted disruption. The BLT2(-/-) mice developed normally, and analysis of immune cells showed that disruption of BLT2 did not alter BLT1 expression or function. Mast cells from the C57BL/6 mice but not from the BLT2(-/-) mice showed intracellular calcium mobilization in response to 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid. In an autoantibody-induced inflammatory arthritis model, the BLT2(-/-) mice showed reduced incidence and severity of disease, including protection from bone and cartilage loss. Reciprocal bone marrow transplant experiments identified that loss of BLT2 expression on a bone marrow-derived cell lineage offers protection against severe disease. Thus, BLT2, a unique receptor for 5-lipoxygenase- and cyclooxygenase-1-derived lipid mediators, represents a novel target for therapies directed at treating inflammation associated with arthritis.

Mathis SP ，Jala VR ，Lee DM ，Haribabu B ... -  《-》

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 《-》

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 《-》