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Science Immunology Dec 2021Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as...
Aeroallergen sensing by airway epithelial cells triggers pathogenic immune responses leading to type 2 inflammation, the hallmark of chronic airway diseases such as asthma. Tuft cells are rare epithelial cells and the dominant source of interleukin-25 (IL-25), an epithelial cytokine, and cysteinyl leukotrienes (CysLTs), lipid mediators of vascular permeability and chemotaxis. How these two mediators derived from the same cell might cooperatively promote type 2 inflammation in the airways has not been clarified. Here, we showed that inhalation of the parent leukotriene C (LTC) in combination with a subthreshold dose of IL-25 led to activation of two innate immune cells: inflammatory type 2 innate lymphoid cell (ILC2) for proliferation and cytokine production, and dendritic cells (DCs). This cooperative effect led to a much greater recruitment of eosinophils and CD4 T cell expansion indicative of synergy. Whereas lung eosinophilia was dominantly mediated through the classical CysLT receptor CysLTR, type 2 cytokines and activation of innate immune cells required signaling through CysLTR and partially CysLTR. Tuft cell–specific deletion of , the terminal enzyme required for CysLT production, reduced lung inflammation and the systemic immune response after inhalation of the mold aeroallergen ; this effect was further enhanced by concomitant blockade of IL-25. Our findings identified a potent synergy of CysLTs and IL-25 downstream of aeroallergen-trigged activation of airway tuft cells leading to a highly polarized type 2 immune response and further implicate airway tuft cells as powerful modulators of type 2 immunity in the lungs.
Topics: Animals; Cysteine; Epithelial Cells; Interleukins; Leukotrienes; Mice; Mice, Transgenic; Pneumonia
PubMed: 34932383
DOI: 10.1126/sciimmunol.abj0474 -
Journal of Internal Medicine Nov 2015The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of... (Review)
Review
The immune reactions that regulate atherosclerotic plaque inflammation involve chemokines, lipid mediators and costimulatory molecules. Chemokines are a family of chemotactic cytokines that mediate immune cell recruitment and control cell homeostasis and activation of different immune cell types and subsets. Chemokine production and activation of chemokine receptors form a positive feedback mechanism to recruit monocytes, neutrophils and lymphocytes into the atherosclerotic plaque. In addition, chemokine signalling affects immune cell mobilization from the bone marrow. Targeting several of the chemokines and/or chemokine receptors reduces experimental atherosclerosis, whereas specific chemokine pathways appear to be involved in plaque regression. Leukotrienes are lipid mediators that are formed locally in atherosclerotic lesions from arachidonic acid. Leukotrienes mediate immune cell recruitment and activation within the plaque as well as smooth muscle cell proliferation and endothelial dysfunction. Antileukotrienes decrease experimental atherosclerosis, and recent observational data suggest beneficial clinical effects of leukotriene receptor antagonism in cardiovascular disease prevention. By contrast, other lipid mediators, such as lipoxins and metabolites of omega-3 fatty acids, have been associated with the resolution of inflammation. Costimulatory molecules play a central role in fine-tuning immunological reactions and mediate crosstalk between innate and adaptive immunity in atherosclerosis. Targeting these interactions is a promising approach for the treatment of atherosclerosis, but immunological side effects are still a concern. In summary, targeting chemokines, leukotriene receptors and costimulatory molecules could represent potential therapeutic strategies to control atherosclerotic plaque inflammation.
Topics: Adaptive Immunity; Animals; Chemokines; Endothelium, Vascular; Humans; Immunity, Cellular; Inflammation; Leukotrienes; Lipoxins; Paracrine Communication; Plaque, Atherosclerotic; Receptors, Chemokine
PubMed: 25823439
DOI: 10.1111/joim.12367 -
The Journal of Allergy and Clinical... Feb 2023Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally... (Review)
Review
Aspirin-exacerbated respiratory disease has fascinated and frustrated specialists in allergy/immunology, pulmonology, and otorhinolaryngology for decades. It generally develops in previously healthy young adults and is unremitting and challenging to treat. The classical triad of asthma, nasal polyposis, and pathognomonic respiratory reactions to aspirin and other cyclooxygenase-1 inhibitors is accompanied by high levels of mast cell activation, cysteinyl leukotriene production, platelet activation, and severe type 2 respiratory inflammation. The "unbraking" of mast cell activation and further cysteinyl leukotriene generation induced by cyclooxygenase-1 inhibition reflect an idiosyncratic dependency on cyclooxygenase-1-derived products, likely prostaglandin E, to maintain a tenuous homeostasis. Although cysteinyl leukotrienes are clear disease effectors, little else was known about their cellular sources and targets, and the contributions from other mediators and type 2 respiratory inflammation effector cells to disease pathophysiology were unknown until recently. The applications of targeted biological therapies, single-cell genomics, and transgenic animal approaches have substantially advanced our understanding of aspirin-exacerbated respiratory disease pathogenesis and treatment and have also revealed disease heterogeneity. This review covers novel insights into the immunopathogenesis of aspirin-exacerbated respiratory disease from each of these lines of research, including the roles of lipid mediators, effector cell populations, and inflammatory cytokines, discusses unanswered questions regarding cause and pathogenesis, and considers potential future therapeutic options.
Topics: Animals; Cyclooxygenase 1; Asthma, Aspirin-Induced; Aspirin; Leukotrienes; Inflammation
PubMed: 36184313
DOI: 10.1016/j.jaci.2022.08.021 -
The Journal of Clinical Investigation Aug 2017Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease...
Leukotrienes are proinflammatory lipid mediators that have been shown to be upregulated in several diseases, including asthma, aspirin-exacerbated respiratory disease (AERD), inflammatory bowel disease, and acute respiratory distress syndrome. Leukotrienes have been explored as therapeutic targets for these diseases and others; however, leukotriene inhibitors have had limited success in the clinic. There are noted differences in the incidence of leukotriene-mediated diseases in males and females, but sex as a factor in the response to leukotriene inhibitors has not been fully explored. In this issue of the JCI, Pace and colleagues present evidence that there are sex-specific differences in the effectiveness of certain leukotriene inhibitors and link the differences in response to the presence of androgens. The results of this study indicate that sex needs to be taken into consideration in the future evaluation of leukotriene inhibitors to treat disease.
Topics: Aspirin; Asthma; Eicosanoids; Female; Humans; Leukotriene Antagonists; Leukotrienes; Male; Platelet Activating Factor
PubMed: 28737507
DOI: 10.1172/JCI95717 -
Journal of Lipid Research Feb 2019Leukotrienes (LTs) are autacoids derived from the precursor arachidonic acid (AA) via the action of five-lipoxygenase (5-LO). When inflammatory cells are activated, 5-LO... (Review)
Review
Leukotrienes (LTs) are autacoids derived from the precursor arachidonic acid (AA) via the action of five-lipoxygenase (5-LO). When inflammatory cells are activated, 5-LO translocates to the nuclear membrane to initiate oxygenation of AA released by cytosolic phospholipase A2 (cPLA2) into leukotriene A (LTA). LTA can also be exported from an activated donor cell into an acceptor cell by the process of transcellular biosynthesis. When thimerosal is added to cells, the level of free AA increases by inhibition of lysophospholipid acyltransferases of the Lands pathway of phospholipid remodeling. Another arachidonate phospholipid cycle involves phosphatidylinositol (PI) in the plasma membrane that undoubtedly intersects with the Lands pathway of phospholipid remodeling. The highest abundance of PI occurs between the ER and the plasma membrane and is probably a result of the importance of the PI signaling cascade in cellular biochemistry. Because transport proteins mediate the rapid intracellular movement of phospholipids, largely as result of physical membrane contact, 5-LO-dependent production of LTA could be mediated by the disappearance of free AA from the nuclear membrane, transfer to the ER for Lands cycle reesterification into PI, and population of PI(18:0/20:4) for cell membrane signaling.
Topics: 1-Acylglycerophosphocholine O-Acyltransferase; Animals; Arachidonic Acid; Humans; Leukotrienes; Phosphatidylinositols
PubMed: 30606731
DOI: 10.1194/jlr.S091371 -
Allergology International : Official... Jan 2020Eosinophils are multifaceted immune cells with diverse functions that enhance allergic inflammation. Cysteinyl leukotrienes (cys-LTs), mainly synthesized in eosinophils,... (Review)
Review
Eosinophils are multifaceted immune cells with diverse functions that enhance allergic inflammation. Cysteinyl leukotrienes (cys-LTs), mainly synthesized in eosinophils, are a class of inflammatory lipid mediators produced via multiple enzymatic reactions from arachidonic acid. Multiple clinical studies have reported dysregulated fatty acid metabolism in severe asthma and aspirin-exacerbated respiratory diseases. Therefore, understanding the mechanism responsible for this metabolic abnormality has attracted a lot of attention. In eosinophils, various stimuli (including cytokines, chemokines, and pathogen-derived factors) prime and/or induce leukotriene generation and secretion. Cell-cell interactions with component cells (endothelial cells, epithelial cells, fibroblasts) also enhance this machinery to augment allergic responses. Nasal polyp-derived eosinophils from patients with eosinophilic rhinosinusitis present a characteristic fatty acid metabolism with selectively higher production of leukotriene D. Interestingly, type 2 cytokines and microbiome components might be responsible for this metabolic change with altered enzyme expression. Here, we review the regulation of fatty acid metabolism, especially cys-LT metabolism, in human eosinophils toward allergic inflammatory status.
Topics: Cysteine; Eosinophils; Humans; Hypersensitivity; Leukotrienes
PubMed: 31248811
DOI: 10.1016/j.alit.2019.06.002 -
Folia Histochemica Et Cytobiologica Jul 2012Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs.... (Review)
Review
Systemic sclerosis (SSc, scleroderma) is an autoimmune disease characterized by widespread vascular injury and progressive fibrosis of the skin and internal organs. SSc-related involvement of the lungs, heart, kidneys and/or the gastrointestinal system accounts for the increased mortality of scleroderma patients. Despite the progress which has recently been made in this field, the treatment of SSc is still unsatisfactory due to the low efficacy and/or high toxicity of available therapies. Leukotrienes are a family of lipid mediators synthesized from arachidonic acid in a process mediated by 5-lipoxygenase; they include leukotriene B4 and a group of cysteinyl leukotrienes: C4, D4, and E4. Leukotrienes play an important role in the regulation of all the processes vital to the pathogenesis of SSc, namely inflammation, vascular function and connective tissue remodeling. The available data suggests that an excessive synthesis of leukotrienes may contribute to the development and progression of SSc. Accordingly, blockade of leukotriene pathways appears to be a new, promising target for the treatment of SSc.
Topics: Biosynthetic Pathways; Humans; Leukotrienes; Scleroderma, Systemic
PubMed: 22763975
DOI: 10.5603/fhc.2012.0027 -
Current Opinion in Allergy and Clinical... Feb 2010Leukotrienes are lipid mediators involved in the pathogenesis of asthma. There is significant new information about the actions of leukotrienes in asthma and the... (Review)
Review
PURPOSE OF REVIEW
Leukotrienes are lipid mediators involved in the pathogenesis of asthma. There is significant new information about the actions of leukotrienes in asthma and the evolving role of antileukotriene therapies. We review recent findings on regulation of leukotriene synthesis, biological function of leukotrienes in disease models, and use of leukotriene modifiers in clinical practice.
RECENT FINDINGS
Our understanding of the regulation of leukotriene synthesis at a molecular level has greatly advanced. Recent evidence indicates that genetic variation in the leukotriene synthetic pathway affects the clinical response to leukotriene modifiers. The participation of leukotriene B4 in the allergic sensitization process in animal models suggests a larger role for leukotriene B4 in asthma. Preclinical and in-vitro models suggest that the cysteinyl leukotrienes are important in airway remodeling. Leukotrienes are key mediators of exercise-induced bronchoconstriction with recent studies demonstrating that leukotriene modifiers reduce the severity of exercise-induced bronchoconstriction during short-term and long-term use.
SUMMARY
Leukotrienes are clearly involved in airway inflammation and certain clinical features of asthma. Evolving evidence indicates that leukotriene B4 has an important role in the development of asthma and that cysteinyl leukotrienes are key mediators of the airway remodeling process.
Topics: Airway Remodeling; Animals; Asthma; Disease Progression; Humans; Leukotriene Antagonists; Leukotrienes; Polymorphism, Genetic
PubMed: 19915456
DOI: 10.1097/ACI.0b013e32833489c3 -
Allergology International : Official... Jan 2015Leukotrienes (LTs), both LTB4 and the cysteinyl LTs (CysLTs) LTC4, LTD4 and LTE4, are implicated in a wide variety of inflammatory disorders. These lipid mediators are... (Review)
Review
Leukotrienes (LTs), both LTB4 and the cysteinyl LTs (CysLTs) LTC4, LTD4 and LTE4, are implicated in a wide variety of inflammatory disorders. These lipid mediators are generated from arachidonic acid via multistep enzymatic reactions through which arachidonic acid is liberated from membrane phospholipids through the action of phospholipase A2. LTB4 and CysLTs exert their biological effects by binding to cognate receptors, which belong to the G protein-coupled receptor superfamily. LTB4 is widely considered to be a potent chemoattractant for most subsets of leukocytes, whereas CysLTs are potent bronchoconstrictors that have effects on airway remodeling. LTs play a central role in the pathogenesis of asthma and many other inflammatory diseases. This review will provide an update on the synthesis, biological function, and relevance of LTs to the pathobiology of allergic diseases, and examine the current and future therapeutic prospects of LT modifiers.
Topics: Animals; Arachidonate 5-Lipoxygenase; Cysteine; Humans; Hypersensitivity; Leukotriene B4; Leukotrienes; Metabolic Networks and Pathways; Receptors, Leukotriene B4
PubMed: 25572555
DOI: 10.1016/j.alit.2014.09.001 -
American Journal of Rhinology & Allergy 2015Aspirin-exacerbated respiratory disease (AERD) is explained in part by overexpression of 5-lipoxygenase and leukotriene C4 synthase (LTC4S), resulting in constitutive... (Review)
Review
BACKGROUND
Aspirin-exacerbated respiratory disease (AERD) is explained in part by overexpression of 5-lipoxygenase and leukotriene C4 synthase (LTC4S), resulting in constitutive overproduction of cysteinyl leukotrienes (CysLTs) and driving the surge in CysLT production that occurs with aspirin ingestion. Similarly, AERD is characterized by the overexpression of CysLT receptors. Increased levels of both interleukin (IL)-4 and interferon (IFN)-γ are present in the tissue of AERD subjects. Previous studies demonstrated that IL-4 is primarily responsible for the up-regulation of LTC4S by mast cells.
METHODS
Literature review.
RESULTS
Our previous studies demonstrated that IFN-γ, but not IL-4, drives this process in eosinophils. These published studies also extend to both IL-4 and IFN-γ the ability to up-regulate CysLT receptors. Prostaglandin E2 (PGE2) acts to prevent CysLT secretion by inhibiting mast cell and eosinophil activation. PGE2 concentrations are reduced in AERD, and our published studies confirm that this reflects diminished expression of cyclooxygenase (COX)-2. A process again that is driven by IL-4. Thus, IL-4 and IFN-γ together play an important pathogenic role in generating the phenotype of AERD. Finally, induction of LTC4S and CysLT1 receptors by IL-4 reflects in part the IL-4-mediated activation of signal transducer and activator of transcription 6 (STAT6). Our previous studies demonstrated that aspirin blocks trafficking of STAT6 into the nucleus and thereby prevents IL-4-mediated induction of these transcripts, thereby suggesting a modality by which aspirin desensitization could provide therapeutic benefit for AERD patients.
CONCLUSION
This review will examine the evidence supporting this model.
Topics: Aspirin; Cysteine; Eosinophilia; Humans; Interferon-gamma; Interleukin-4; Leukotriene E4; Leukotrienes; Mast Cells; Phenotype; Receptors, Leukotriene; Receptors, Prostaglandin E; Respiratory Tract Diseases
PubMed: 25590316
DOI: 10.2500/ajra.2015.29.4123