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Nature Aug 2023The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with...
The physiological functions of mast cells remain largely an enigma. In the context of barrier damage, mast cells are integrated in type 2 immunity and, together with immunoglobulin E (IgE), promote allergic diseases. Allergic symptoms may, however, facilitate expulsion of allergens, toxins and parasites and trigger future antigen avoidance. Here, we show that antigen-specific avoidance behaviour in inbred mice is critically dependent on mast cells; hence, we identify the immunological sensor cell linking antigen recognition to avoidance behaviour. Avoidance prevented antigen-driven adaptive, innate and mucosal immune activation and inflammation in the stomach and small intestine. Avoidance was IgE dependent, promoted by Th2 cytokines in the immunization phase and by IgE in the execution phase. Mucosal mast cells lining the stomach and small intestine rapidly sensed antigen ingestion. We interrogated potential signalling routes between mast cells and the brain using mutant mice, pharmacological inhibition, neural activity recordings and vagotomy. Inhibition of leukotriene synthesis impaired avoidance, but overall no single pathway interruption completely abrogated avoidance, indicating complex regulation. Collectively, the stage for antigen avoidance is set when adaptive immunity equips mast cells with IgE as a telltale of past immune responses. On subsequent antigen ingestion, mast cells signal termination of antigen intake. Prevention of immunopathology-causing, continuous and futile responses against per se innocuous antigens or of repeated ingestion of toxins through mast-cell-mediated antigen-avoidance behaviour may be an important arm of immunity.
Topics: Animals; Mice; Allergens; Avoidance Learning; Hypersensitivity; Immunoglobulin E; Mast Cells; Stomach; Vagotomy; Immunity, Innate; Immunity, Mucosal; Th2 Cells; Cytokines; Leukotrienes; Intestine, Small
PubMed: 37438525
DOI: 10.1038/s41586-023-06188-0 -
International Journal of Molecular... Dec 2021Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated... (Review)
Review
Cancer remains a leading cause of death worldwide, despite many advances being made in recent decades. Changes in the tumor microenvironment, including dysregulated immunity, may contribute to carcinogenesis and cancer progression. The cysteinyl leukotriene (CysLT) pathway is involved in several signal pathways, having various functions in different tissues. We summarized major findings of studies about the roles of the CysLT pathway in cancer. Many in vitro studies suggested the roles of CysLTs in cell survival/proliferation via CysLT receptor (CysLTR). CysLTR antagonism decreased cell vitality and induced cell death in several types of cancer cells, such as colorectal, urological, breast, lung and neurological malignancies. CysLTs were also associated with multidrug resistance of cancer, and CysLTR antagonism might reverse chemoresistance. Some animal studies demonstrated the beneficial effects of CysLTR antagonist in inhibiting tumorigenesis and progression of some cancer types, particularly colorectal cancer and lung cancer. The expression of CysLTR was shown in various cancer tissues, particularly colorectal cancer and urological malignancies, and higher expression was associated with a poorer prognosis. The chemo-preventive effects of CysLTR antagonists were demonstrated in two large retrospective cohort studies. In summary, the roles of the CysLT pathway in cancer have been delineated, whereas further studies are still warranted.
Topics: Animals; Apoptosis; Cell Proliferation; Cysteine; Humans; Leukotrienes; Neoplasms; Retrospective Studies; Signal Transduction
PubMed: 35008546
DOI: 10.3390/ijms23010120 -
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 -
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 -
Prostaglandins & Other Lipid Mediators Jun 20195-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and... (Review)
Review
5-lipoxygenase (5-LO) is the key enzyme in the biosynthesis of leukotrienes and specialized proresolving lipid mediators (SPM). It is mainly expressed in leukocytes and is part of the innate immune system. 5-LO can shuttle between the cytosol and the nucleus. Upon cell activation the protein translocates from soluble cellular compartments to the nuclear membrane. Besides FLAP which is required for cellular leukotriene and SPM formation, 5-LO interacts with other proteins like coactosin-like protein (CLP), Dicer, β-catenin and p53. In this review, the factors involved in the regulation of 5-LO expression, the role of 5-LO in the regulation of stem cell proliferation and differentiation and its biological functions apart from leukotriene and SPM formation are summarized.
Topics: Animals; Arachidonate 5-Lipoxygenase; Gene Expression Regulation, Enzymologic; Humans; Leukotrienes; Tumor Suppressor Protein p53; Wnt Signaling Pathway
PubMed: 30930090
DOI: 10.1016/j.prostaglandins.2019.03.003 -
Current Opinion in Nephrology and... Jan 2018This review will critically highlight the role of leukotrienes as mediators of renal diseases and drug nephrotoxicity. It will also discuss the recently identified... (Review)
Review
PURPOSE OF REVIEW
This review will critically highlight the role of leukotrienes as mediators of renal diseases and drug nephrotoxicity. It will also discuss the recently identified mechanism of cysteinyl leukotrienes induction and action, and will propose clinical implementation of these findings.
RECENT FINDINGS
Since last reviewed in 1994, leukotrienes were shown to mediate drug-associated nephrotoxicity, transplant rejection and morbidity in several models of renal diseases. Although leukotrienes may be released by various infiltrating leukocytes, a recent study demonstrated that cytotoxic agents trigger production of leukotriene C4 (LTC4) in mouse kidney cells by activating a biosynthetic pathway based on microsomal glutathione-S-transferase 2 (MGST2). LTC4 then elicits nuclear accumulation of hydrogen peroxide-generating NADPH oxidase 4, leading to oxidative DNA damage and cell death. LTC4 inhibitors, commonly used as systemic asthma drugs, alleviated drug-associated damage to proximal tubular cells and attenuated mouse morbidity.
SUMMARY
Cysteinyl leukotrienes released by mast cells trigger the symptoms of asthma, including bronchoconstriction and vasoconstriction. Therefore, effective leukotriene inhibitors were approved as orally administered asthma drugs. The findings that leukotrienes mediate the cytotoxicity of nephrotoxic drugs, and are involved in numerous renal diseases, suggest that such asthma drugs may ameliorate drug-induced nephrotoxicity, as well as some renal diseases.
Topics: Animals; Anti-Asthmatic Agents; Cell Death; Cysteine; DNA Damage; Glutathione Transferase; Humans; Kidney Diseases; Leukotriene Antagonists; Leukotriene C4; Leukotrienes; NADPH Oxidase 4; Oxidative Stress
PubMed: 29059080
DOI: 10.1097/MNH.0000000000000381 -
Annual Review of Pharmacology and... Jan 2023Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also... (Review)
Review
Leukotrienes are potent immune-regulating lipid mediators with patho-genic roles in inflammatory and allergic diseases, particularly asthma. These autacoids also contribute to low-grade inflammation, a hallmark of cardiovascular, neurodegenerative, metabolic, and tumor diseases. Biosynthesis of leukotrienes involves release and oxidative metabolism of arachidonic acid and proceeds via a set of cytosolic and integral membrane enzymes that are typically expressed by cells of the innate immune system. In activated cells, these enzymes traffic and assemble at the endoplasmic and perinuclear membrane, together comprising a biosynthetic complex. Here we describe recent advances in our molecular understanding of the protein components of the leukotriene-synthesizing enzyme machinery and also briefly touch upon the leukotriene receptors. Moreover, we discuss emerging opportunities for pharmacological intervention and development of new therapeutics.
Topics: Humans; Leukotrienes; Inflammation; Asthma
PubMed: 36130059
DOI: 10.1146/annurev-pharmtox-051921-085014 -
Annual Review of Physiology Feb 2018The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic... (Review)
Review
The lymphatic system is essential for the maintenance of tissue fluid homeostasis, gastrointestinal lipid absorption, and immune trafficking. Whereas lymphatic regeneration occurs physiologically in wound healing and tissue repair, pathological lymphangiogenesis has been implicated in a number of chronic diseases such as lymphedema, atherosclerosis, and cancer. Insight into the regulatory mechanisms of lymphangiogenesis and the manner in which uncontrolled inflammation promotes lymphatic dysfunction is urgently needed to guide the development of novel therapeutics: These would be designed to reverse lymphatic dysfunction, either primary or acquired. Recent investigation has demonstrated the mechanistic role of leukotriene B (LTB) in the molecular pathogenesis of lymphedema. LTB, a product of the innate immune response, is a constituent of the eicosanoid inflammatory mediator family of molecules that promote both physiological and pathological inflammation. Here we provide an overview of lymphatic development, the pathophysiology of lymphedema, and the role of leukotrienes in lymphedema pathogenesis.
Topics: Animals; Humans; Inflammation; Leukotrienes; Lymphatic System; Lymphedema
PubMed: 29029593
DOI: 10.1146/annurev-physiol-022516-034008 -
Biomolecules Feb 2022Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging... (Review)
Review
Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are two common types of α-synucleinopathies and represent a high unmet medical need. Despite diverging clinical manifestations, both neurodegenerative diseases share several facets of their complex pathophysiology. Apart from α-synuclein aggregation, an impairment of mitochondrial functions, defective protein clearance systems and excessive inflammatory responses are consistently observed in the brains of PD as well as DLB patients. Leukotrienes are lipid mediators of inflammatory signaling traditionally known for their role in asthma. However, recent research advances highlight a possible contribution of leukotrienes, along with their rate-limiting synthesis enzyme 5-lipoxygenase, in the pathogenesis of central nervous system disorders. This review provides an overview of in vitro as well as in vivo studies, in summary suggesting that dysregulated leukotriene signaling is involved in the pathological processes underlying PD and DLB. In addition, we discuss how the leukotriene signaling pathway could serve as a future drug target for the therapy of PD and DLB.
Topics: Brain; Humans; Leukotrienes; Lewy Body Disease; Parkinson Disease; Signal Transduction; Synucleinopathies; alpha-Synuclein
PubMed: 35327537
DOI: 10.3390/biom12030346 -
British Journal of Pharmacology Nov 2022Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has... (Review)
Review
Cysteinyl leukotrienes (CysLTs) are inflammatory lipid mediators that play a central role in the pathophysiology of several inflammatory diseases. Recently, there has been an increased interest in determining how these lipid mediators orchestrate tumour development and metastasis through promoting a pro-tumour micro-environment. Up-regulation of CysLTs receptors and CysLTs production is found in a number of cancers and has been associated with increased tumorigenesis. Understanding the molecular mechanisms underlying the role of CysLTs and their receptors in cancer progression will help investigate the potential of targeting CysLTs signalling for anti-cancer therapy. This review gives an overview of the biological effects of CysLTs and their receptors, along with current knowledge of their regulation and expression. It also provides a recent update on the molecular mechanisms that have been postulated to explain their role in tumorigenesis and on the potential of anti-CysLTs in the treatment of cancer.
Topics: Carcinogenesis; Cysteine; Humans; Leukotrienes; Neoplasms; Tumor Microenvironment
PubMed: 33527344
DOI: 10.1111/bph.15402