-
Proceedings of the National Academy of... Mar 2021Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms...
Acute and chronic itch are burdensome manifestations of skin pathologies including allergic skin diseases and atopic dermatitis, but the underlying molecular mechanisms are not well understood. Cysteinyl leukotrienes (CysLTs), comprising LTC, LTD, and LTE, are produced by immune cells during type 2 inflammation. Here, we uncover a role for LTC and its signaling through the CysLT receptor 2 (CysLTR) in itch. transcript is highly expressed in dorsal root ganglia (DRG) neurons linked to itch in mice. We also detected in a broad population of human DRG neurons. Injection of leukotriene C (LTC) or its nonhydrolyzable form NMLTC, but neither LTD nor LTE, induced dose-dependent itch but not pain behaviors in mice. LTC-mediated itch differed in bout duration and kinetics from pruritogens histamine, compound 48/80, and chloroquine. NMLTC-induced itch was abrogated in mice deficient for or when deficiency was restricted to radioresistant cells. Itch was unaffected in mice deficient for , , or mast cells (W mice). CysLTR played a role in itch in the MC903 mouse model of chronic itch and dermatitis, but not in models of dry skin or compound 48/80- or -induced itch. In MC903-treated mice, CysLT levels increased in skin over time, and mice showed decreased itch in the chronic phase of inflammation. Collectively, our study reveals that LTC acts through CysLTR as its physiological receptor to induce itch, and CysLTR contributes to itch in a model of dermatitis. Therefore, targeting CysLT signaling may be a promising approach to treat inflammatory itch.
Topics: Animals; Chronic Disease; Dermatitis, Atopic; Disease Models, Animal; Ganglia, Spinal; Humans; Leukotriene C4; Mice; Mice, Knockout; Pruritus; Receptors, Leukotriene; Sensory Receptor Cells; Signal Transduction; Skin
PubMed: 33753496
DOI: 10.1073/pnas.2022087118 -
The Journal of Clinical Investigation Jul 2018Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug... (Review)
Review
Leukotrienes, a class of arachidonic acid-derived bioactive molecules, are known as mediators of allergic and inflammatory reactions and considered to be important drug targets. Although an inhibitor of leukotriene biosynthesis and antagonists of the cysteinyl leukotriene receptor are clinically used for bronchial asthma and allergic rhinitis, these medications were developed before the molecular identification of leukotriene receptors. Numerous studies using cloned leukotriene receptors and genetically engineered mice have unveiled new pathophysiological roles for leukotrienes. This Review covers the recent findings on leukotriene receptors to revisit them as new drug targets.
Topics: Animals; Arthritis, Experimental; Asthma; Atherosclerosis; Chemotaxis, Leukocyte; Humans; Leukotriene Antagonists; Mice; Models, Biological; Models, Molecular; Molecular Structure; Neoplasms; Receptors, Leukotriene; Receptors, Leukotriene B4; Signal Transduction
PubMed: 29757196
DOI: 10.1172/JCI97946 -
Nature Communications May 2023Hepatocellular carcinoma (HCC) is the 3 most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are...
Hepatocellular carcinoma (HCC) is the 3 most deadly malignancy. Activated hepatic stellate cells (aHSC) give rise to cancer-associated fibroblasts in HCC and are considered a potential therapeutic target. Here we report that selective ablation of stearoyl CoA desaturase-2 (Scd2) in aHSC globally suppresses nuclear CTNNB1 and YAP1 in tumors and tumor microenvironment and prevents liver tumorigenesis in male mice. Tumor suppression is associated with reduced leukotriene B4 receptor 2 (LTB4R2) and its high affinity oxylipin ligand, 12-hydroxyheptadecatrienoic acid (12-HHTrE). Genetic or pharmacological inhibition of LTB4R2 recapitulates CTNNB1 and YAP1 inactivation and tumor suppression in culture and in vivo. Single cell RNA sequencing identifies a subset of tumor-associated aHSC expressing Cyp1b1 but no other 12-HHTrE biosynthetic genes. aHSC release 12-HHTrE in a manner dependent on SCD and CYP1B1 and their conditioned medium reproduces the LTB4R2-mediated tumor-promoting effects of 12-HHTrE in HCC cells. CYP1B1-expressing aHSC are detected in proximity of LTB4R2-positive HCC cells and the growth of patient HCC organoids is blunted by LTB4R2 antagonism or knockdown. Collectively, our findings suggest aHSC-initiated 12-HHTrE-LTB4R2-CTNNB1-YAP1 pathway as a potential HCC therapeutic target.
Topics: Animals; Male; Mice; beta Catenin; Carcinogenesis; Carcinoma, Hepatocellular; Fatty Acid Desaturases; Hepatic Stellate Cells; Liver Neoplasms; Receptors, Leukotriene B4; Tumor Microenvironment
PubMed: 37156770
DOI: 10.1038/s41467-023-38406-8 -
Seminars in Immunology Oct 2017Leukotriene B (LTB), a lipid mediator produced from arachidonic acid, is a chemoattractant for inflammatory leukocytes. We identified two receptors for LTB, the... (Review)
Review
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.
Topics: Animals; Cell Movement; Chemotaxis; Fatty Acids, Unsaturated; Humans; Inflammation; Intestinal Mucosa; Leukocytes; Leukotriene B4; Mice; Mice, Knockout; Receptors, Leukotriene B4; Signal Transduction; Skin
PubMed: 29042026
DOI: 10.1016/j.smim.2017.07.010 -
Nature Communications Mar 2022Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, the mechanism...
Leukotriene B4 receptor 1 (BLT1) plays crucial roles in the acute inflammatory responses and is a valuable target for anti-inflammation treatment, however, the mechanism by which leukotriene B4 (LTB4) activates receptor remains unclear. Here, we report the cryo-electron microscopy (cryo-EM) structure of the LTB4 -bound human BLT1 in complex with a G protein in an active conformation at resolution of 2.91 Å. In combination of molecule dynamics (MD) simulation, docking and site-directed mutagenesis, our structure reveals that a hydrogen-bond network of water molecules and key polar residues is the key molecular determinant for LTB4 binding. We also find that the displacement of residues M101 and I271 to the center of receptor, which unlock the ion lock of the lower part of pocket, is the key mechanism of receptor activation. In addition, we reveal a binding site of phosphatidylinositol (PI) and discover that the widely open ligand binding pocket may contribute the lack of specificity and efficacy for current BLT1-targeting drug design. Taken together, our structural analysis provides a scaffold for understanding BLT1 activation and a rational basis for designing anti-leukotriene drugs.
Topics: Cryoelectron Microscopy; GTP-Binding Proteins; Humans; Inflammation; Leukotriene B4; Receptors, Leukotriene B4; Signal Transduction; Structure-Activity Relationship
PubMed: 35241677
DOI: 10.1038/s41467-022-28820-9 -
Seminars in Immunology Oct 2017For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous... (Review)
Review
For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous metabolites in the blood, sputum, and bronchoalveolar lavage fluid from asthmatics or experimental animals adds support to this notion. However, targeting of the leukotriene pathways has had, in general, limited success. The single exception in asthma therapy has been targeting of the cysteinyl leukotriene receptor 1, which clinically has proven effective but only in certain clinical situations. Interference with 5-lipoxygenase has had limited success, in part due to adverse drug effects. The importance of the LTB4-BLT1 pathway in asthma pathogenesis has extensive experimental support and findings, albeit limited, from clinical samples. The LTB4-BLT1 pathway was shown to be important as a neutrophil chemoattractant. Despite observations made more than two decades ago, the LTB4-BLT1 pathway has only recently been shown to exhibit important activities on subsets of T lymphocytes, both as a chemoattractant and on lymphocyte activation, as well as on dendritic cells, the major antigen presenting cell in the lung. The role of BLT2 in asthma remains unclear. Targeting of components of the LTB4-BLT1 pathway offers innovative therapeutic opportunities especially in patients with asthma that remain uncontrolled despite intensive corticosteroid treatment.
Topics: Animals; Asthma; Chemotaxis; Dendritic Cells; Humans; Leukotriene B4; Lymphocyte Activation; Neutrophils; Receptors, Leukotriene B4; Signal Transduction; T-Lymphocytes
PubMed: 29042028
DOI: 10.1016/j.smim.2017.08.005 -
Cells Feb 2021Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular... (Review)
Review
Retinal vascular diseases have distinct, complex and multifactorial pathogeneses yet share several key pathophysiological aspects including inflammation, vascular permeability and neovascularisation. In non-infectious posterior uveitis (NIU), retinal vasculitis involves vessel leakage leading to retinal enlargement, exudation, and macular oedema. Neovascularisation is not a common feature in NIU, however, detection of the major angiogenic factor-vascular endothelial growth factor A (VEGF-A)-in intraocular fluids in animal models of uveitis may be an indication for a role for this cytokine in a highly inflammatory condition. Suppression of VEGF-A by directly targeting the leukotriene B4 (LTB4) receptor (BLT1) pathway indicates a connection between leukotrienes (LTs), which have prominent roles in initiating and propagating inflammatory responses, and VEGF-A in retinal inflammatory diseases. Further research is needed to understand how LTs interact with intraocular cytokines in retinal inflammatory diseases to guide the development of novel therapeutic approaches targeting both inflammatory mediator pathways.
Topics: Animals; Disease Models, Animal; Humans; Inflammation; Receptors, Leukotriene B4; Retinal Vasculitis; Uveitis; Vascular Endothelial Growth Factor A
PubMed: 33671954
DOI: 10.3390/cells10020396 -
Aging Dec 2021Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal...
Autophagy is an important cellular mechanism for maintaining cellular homeostasis, and its impairment correlates highly with age and age-related diseases. Retinal pigment epithelial (RPE) cells of the eye represent a crucial model for studying autophagy, as RPE functions and integrity are highly dependent on an efficient autophagic process. Cysteinyl leukotriene receptor 1 (CysLTR1) acts in immunoregulation and cellular stress responses and is a potential regulator of basal and adaptive autophagy. As basal autophagy is a dynamic process, the aim of this study was to define the role of CysLTR1 in autophagy regulation in a chronobiologic context using the ARPE-19 human RPE cell line. Effects of CysLTR1 inhibition on basal autophagic activity were analyzed at inactive/low and high lysosomal degradation activity with the antagonists zafirlukast (ZTK) and montelukast (MTK) at a dosage of 100 nM for 3 hours. Abundances of the autophagy markers LC3-II and SQSTM1 and LC3B particles were analyzed in the absence and presence of lysosomal inhibitors using western blot analysis and immunofluorescence microscopy. CysLTR1 antagonization revealed a biphasic effect of CysLTR1 on autophagosome formation and lysosomal degradation that depended on the autophagic activity of cells at treatment initiation. ZTK and MTK affected lysosomal degradation, but only ZTK regulated autophagosome formation. In addition, dexamethasone treatment and serum shock induced autophagy, which was repressed by CysLTR1 antagonization. As a newly identified autophagy modulator, CysLTR1 appears to be a key player in the chronobiological regulation of basal autophagy and adaptive autophagy in RPE cells.
Topics: Acetates; Autophagy; Blotting, Western; Cell Line; Cell Survival; Chronobiology Phenomena; Cyclopropanes; Epithelial Cells; Humans; Indoles; Leukotriene Antagonists; Oxidative Stress; Phenylcarbamates; Quinolines; Receptors, Leukotriene; Retinal Pigment Epithelium; Sulfides; Sulfonamides
PubMed: 34919533
DOI: 10.18632/aging.203787 -
Cardiovascular Drugs and Therapy Feb 2009The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by... (Review)
Review
INTRODUCTION
The inflammatory process of atherosclerosis is associated with several pathophysiological reactions within the vascular wall. The arachidonic acid released by phospholipase A(2) serves as substrate for the production of a group of lipid mediators known as the leukotrienes, which induce pro-inflammatory signaling through activation of specific BLT and CysLT receptors.
DISCUSSION
Leukotriene signaling has been implicated in early lipid retention and foam cell accumulation, as well as in the development of intimal hyperplasia and advanced atherosclerotic lesions. Furthermore, the association of leukotrienes with degradation of extracellular matrix has suggested a role in atherosclerotic plaque rupture. Finally, studies of either myocardial or cerebral ischemia and reperfusion indicate that leukotriene signaling in addition may be involved in the development of ischemic injury.
CONCLUSION
Both leukotriene synthesis inhibitors and leukotriene receptor antagonists have been suggested to induce beneficial effects at different stages of the atherosclerosis process.
Topics: Animals; Atherosclerosis; Brain Ischemia; Humans; Leukotriene Antagonists; Leukotrienes; Myocardial Ischemia; Receptors, Leukotriene; Signal Transduction
PubMed: 18949546
DOI: 10.1007/s10557-008-6140-9 -
The Journal of Allergy and Clinical... Sep 2009Leukotrienes are now established contributors to the inflammatory process in asthma, and leukotriene modifiers are mainstays in the therapy of asthma. This review... (Review)
Review
Leukotrienes are now established contributors to the inflammatory process in asthma, and leukotriene modifiers are mainstays in the therapy of asthma. This review focuses on published association studies implicating the role of leukotriene pathway genes in asthma pathogenesis and treatment response, specifically focusing on those genetic variants associated with asthma affection status, the development of aspirin-exacerbated respiratory disease, and pharmacogenetic response. Although published studies have been limited by small sample sizes and a lack of independent replication, multiple loci within multiple leukotriene pathway genes have now been associated in more than 1 study related to asthma or asthma treatment response. Those specific variants include 2 variants in the 5-lipoxygenase gene (ALOX5) that are both associated with response to 5-lipoxygenase inhibition and to leukotriene receptor antagonists, variants in genes encoding the 2 established cysteinyl leukotriene receptor antagonists (CYSLTR1 and CYSLTR2) that are both associated with asthma susceptibility in at least 2 independent populations, and a leukotriene C(4) synthase promoter polymorphism (LTC4s) that has been associated with asthma affection status and asthma-exacerbated respiratory disease. Despite these successes, genetic investigations into this pathway remain in their formative stages. Future studies aimed at providing a broader scope of investigation through increased sample sizes and through genome-wide approaches are needed.
Topics: Animals; Anti-Asthmatic Agents; Arachidonate 5-Lipoxygenase; Asthma; Humans; Leukotriene Antagonists; Leukotrienes; Receptors, Leukotriene
PubMed: 19665766
DOI: 10.1016/j.jaci.2009.06.035