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Science Immunology Mar 2023IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne...
IgE-mediated anaphylaxis is an acute life-threatening systemic reaction to allergens, including certain foods and venoms. Anaphylaxis is triggered when blood-borne allergens activate IgE-bound perivascular mast cells (MCs) throughout the body, causing an extensive systemic release of MC mediators. Through precipitating vasodilatation and vascular leakage, these mediators are believed to trigger a sharp drop in blood pressure in humans and in core body temperature in animals. We report that the IgE/MC-mediated drop in body temperature in mice associated with anaphylaxis also requires the body's thermoregulatory neural circuit. This circuit is activated when granule-borne chymase from MCs is deposited on proximal TRPV1 sensory neurons and stimulates them via protease-activated receptor-1. This triggers the activation of the body's thermoregulatory neural network, which rapidly attenuates brown adipose tissue thermogenesis to cause hypothermia. Mice deficient in either chymase or TRPV1 exhibited limited IgE-mediated anaphylaxis, and, in wild-type mice, anaphylaxis could be recapitulated simply by systemically activating TRPV1 sensory neurons. Thus, in addition to their well-known effects on the vasculature, MC products, especially chymase, promote IgE-mediated anaphylaxis by activating the thermoregulatory neural circuit.
Topics: Mice; Humans; Animals; Anaphylaxis; Chymases; Mast Cells; Hypothermia; Immunoglobulin E; Allergens; Neurons
PubMed: 36930731
DOI: 10.1126/sciimmunol.adc9417 -
Journal of Innate Immunity 2020
Topics: Chymases; Humans; Immunity, Innate; Immunity, Mucosal; Inflammatory Bowel Diseases; Macrophages; Mast Cells; Membrane Glycoproteins; Mucosal-Associated Invariant T Cells; Mucous Membrane; Receptors, Interleukin-1
PubMed: 32818941
DOI: 10.1159/000510316 -
International Journal of Molecular... Dec 2020A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation,... (Review)
Review
A sizable part (~2%) of the human genome encodes for proteases. They are involved in many physiological processes, such as development, reproduction and inflammation, but also play a role in pathology. Mast cells (MC) contain a variety of MC specific proteases, the expression of which may differ between various MC subtypes. Amongst these proteases, chymase represents up to 25% of the total proteins in the MC and is released from cytoplasmic granules upon activation. Once secreted, it cleaves the targets in the local tissue environment, but may also act in lymph nodes infiltrated by MC, or systemically, when reaching the circulation during an inflammatory response. MC have been recognized as important components in the development of kidney disease. Based on this observation, MC chymase has gained interest following the discovery that it contributes to the angiotensin-converting enzyme's independent generation of angiotensin II, an important inflammatory mediator in the development of kidney disease. Hence, progress regarding its role has been made based on studies using inhibitors but also on mice deficient in MC protease 4 (mMCP-4), the functional murine counterpart of human chymase. In this review, we discuss the role and actions of chymase in kidney disease. While initially believed to contribute to pathogenesis, the accumulated data favor a more subtle view, indicating that chymase may also have beneficial actions.
Topics: Angiotensin II; Animals; Biomarkers; Chymases; Disease Management; Disease Susceptibility; Humans; Kidney Diseases; Mast Cells; Molecular Targeted Therapy; Nephritis; Serine Proteinase Inhibitors
PubMed: 33396702
DOI: 10.3390/ijms22010302 -
American Journal of Physiology. Lung... Mar 2021The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge... (Review)
Review
The unique clinical features of COVID-19 disease present a formidable challenge in the understanding of its pathogenesis. Within a very short time, our knowledge regarding basic physiological pathways that participate in SARS-CoV-2 invasion and subsequent organ damage have been dramatically expanded. In particular, we now better understand the complexity of the renin-angiotensin-aldosterone system (RAAS) and the important role of angiotensin converting enzyme (ACE)-2 in viral binding. Furthermore, the critical role of its major product, angiotensin (Ang)-(1-7), in maintaining microcirculatory balance and in the control of activated proinflammatory and procoagulant pathways, generated in this disease, have been largely clarified. The kallikrein-bradykinin (BK) system and chymase are intensively interwoven with RAAS through many pathways with complex reciprocal interactions. Yet, so far, very little attention has been paid to a possible role of these physiological pathways in the pathogenesis of COVID-19 disease, even though BK and chymase exert many physiological changes characteristic to this disorder. Herein, we outline the current knowledge regarding the reciprocal interactions of RAAS, BK, and chymase that are probably turned-on in COVID-19 disease and participate in its clinical features. Interventions affecting these systems, such as the inhibition of chymase or blocking BKB1R/BKB2R, might be explored as potential novel therapeutic strategies in this devastating disorder.
Topics: COVID-19; Chymases; Humans; Kinins; Renin-Angiotensin System; SARS-CoV-2
PubMed: 33404363
DOI: 10.1152/ajplung.00548.2020 -
Current Pharmaceutical Design 2013Mast cells are critical effectors in inflammatory diseases, including cardiovascular and metabolic diseases and their associated complications. These cells exert their... (Review)
Review
Mast cells are critical effectors in inflammatory diseases, including cardiovascular and metabolic diseases and their associated complications. These cells exert their physiological and pathological activities by releasing granules containing histamine, cytokines, chemokines, and proteases, including mast cell-specific chymases and tryptases. Several recent human and animal studies have shown direct or indirect participation of mast cell-specific proteases in atherosclerosis, abdominal aortic aneurysms, obesity, diabetes, and their complications. Animal studies have demonstrated the beneficial effects of highly selective and potent chymase and tryptase inhibitors in several experimental cardiovascular and metabolic diseases. In this review, we summarize recent discoveries from in vitro cell-based studies to experimental animal disease models, from protease knockout mice to treatments with recently developed selective and potent protease inhibitors, and from patients with preclinical disorders to those affected by complications. We hypothesize that inhibition of chymases and tryptases would benefit patients suffering from cardiovascular and metabolic diseases.
Topics: Animals; Cardiovascular Diseases; Chymases; Enzyme Inhibitors; Humans; Mast Cells; Metabolic Diseases; Mice; Tryptases
PubMed: 23016684
DOI: 10.2174/1381612811319060012 -
Journal of Neuroinflammation Aug 2022Asthma is a major public health problem worldwide. Emerging data from epidemiological studies show that allergies and allergic diseases may be linked to anxiety,...
BACKGROUND
Asthma is a major public health problem worldwide. Emerging data from epidemiological studies show that allergies and allergic diseases may be linked to anxiety, depression and cognitive decline. However, little is known about the effect of asthma, an allergic lung inflammation, on cognitive decline/behavioral changes. Therefore, we investigated the hypothesis that allergic lung inflammation causes inflammation in the brain and leads to neurobehavioral changes in mice.
METHODS
Wild-type C57BL/6J female mice were sensitized with nasal house dust mite (HDM) antigen or control PBS for 6 weeks to induce chronic allergic lung inflammation. A series of neurocognitive tests for anxiety and/or depression were performed before and after the intranasal HDM administration. After the behavior tests, tissues were harvested to measure inflammation in the lungs and the brains.
RESULTS
HDM-treated mice exhibited significantly increased immobility times during tail suspension tests and significantly decreased sucrose preference compared with PBS controls, suggesting a more depressed and anhedonia phenotype. Spatial memory impairment was also observed in HDM-treated mice when assessed by the Y-maze novel arm tests. Development of lung inflammation after 6 weeks of HDM administration was confirmed by histology, bronchoalveolar lavage (BAL) cell count and lung cytokine measurements. Serum pro-inflammatory cytokines and Th2-related cytokines levels were elevated in HDM-sensitized mice. In the brain, the chemokine fractalkine was increased in the HDM group. The c-Fos protein, a marker for neuronal activity, Glial Fibrillary Acidic Protein (GFAP) and chymase, a serine protease from mast cells, were increased in the brains from mice in HDM group. Chymase expression in the brain was negatively correlated with the results of sucrose preference rate in individual mice.
CONCLUSIONS
6 weeks of intranasal HDM administration in mice to mimic the chronic status of lung inflammation in asthma, caused significant inflammatory histological changes in the lungs, and several behavioral changes consistent with depression and altered spatial memory. Chymase and c-Fos proteins were increased in the brain from HDM-treated mice, suggesting links between lung inflammation and brain mast cell activation, which could be responsible for depression-like behavior.
Topics: Animals; Asthma; Bronchoalveolar Lavage Fluid; Chymases; Cytokines; Disease Models, Animal; Female; Hypersensitivity; Inflammation; Lung; Mice; Mice, Inbred C57BL; Pneumonia; Pyroglyphidae; Sucrose; Th2 Cells
PubMed: 36045388
DOI: 10.1186/s12974-022-02575-y -
Frontiers in Immunology 2022Proteases are stored in very large amounts within abundant cytoplasmic granules of mast cells (MCs), and in lower amounts in basophils. These proteases are stored in... (Review)
Review
Proteases are stored in very large amounts within abundant cytoplasmic granules of mast cells (MCs), and in lower amounts in basophils. These proteases are stored in their active form in complex with negatively charged proteoglycans, such as heparin and chondroitin sulfate, ready for rapid release upon MC and basophil activation. The absolute majority of these proteases belong to the large family of chymotrypsin related serine proteases. Three such enzymes are found in human MCs, a chymotryptic enzyme, the chymase, a tryptic enzyme, the tryptase and cathepsin G. Cathepsin G has in primates both chymase and tryptase activity. MCs also express a MC specific exopeptidase, carboxypeptidase A3 (CPA3). The targets and thereby the functions of these enzymes have for many years been the major question of the field. However, the fact that some of these enzymes have a relatively broad specificity has made it difficult to obtain reliable information about the biologically most important targets for these enzymes. Under optimal conditions they may cleave a relatively large number of potential targets. Three of these enzymes, the chymase, the tryptase and CPA3, have been shown to inactivate several venoms from snakes, scorpions, bees and Gila monster. The chymase has also been shown to cleave several connective tissue components and thereby to be an important player in connective tissue homeostasis. This enzyme can also generate angiotensin II (Ang II) by cleavage of Ang I and have thereby a role in blood pressure regulation. It also display anticoagulant activity by cleaving fibrinogen and thrombin. A regulatory function on excessive T2 immunity has also been observed for both the chymase and the tryptase by cleavage of a highly selective set of cytokines and chemokines. The chymase also appear to have a protective role against ectoparasites such as ticks, mosquitos and leeches by the cleavage of their anticoagulant proteins. We here review the data that has accumulated concerning the potential functions of these enzymes and we discuss how this information sheds new light on the role of MCs and basophils in health and disease.
Topics: Animals; Anticoagulants; Basophils; Bees; Cathepsin G; Chymases; Cytoplasmic Granules; Humans; Mast Cells; Peptide Hydrolases; Tryptases
PubMed: 35865537
DOI: 10.3389/fimmu.2022.918305 -
Bioengineered May 2022When mosquitoes probe to feed blood, they inoculate a mixture of salivary molecules into vertebrate hosts' skin causing acute inflammatory reactions where mast...
When mosquitoes probe to feed blood, they inoculate a mixture of salivary molecules into vertebrate hosts' skin causing acute inflammatory reactions where mast cell-derived mediators are involved. Mosquito saliva contains many proteins with largely unknown biological functions. Here, two salivary proteins - adenosine deaminase (alADA) and al34k2 - were investigated for their immunological impact on mast cells and two mast cell-specific proteases, the tryptase and the chymase. Mouse bone marrow-derived mast cells were challenged with increased concentrations of recombinant alADA or al34k2 for 1, 3, and 6 h, and to measure mast cell activation, the activity levels of β-hexosaminidase and tryptase and secretion of IL-6 were evaluated. In addition, a direct interaction between alADA or al34k2 with tryptase or chymase was investigated. Results show that bone marrow-derived mast cells challenged with 10 μg/ml of alADA secreted significant levels of β-hexosaminidase, tryptase, and IL-6. Furthermore, both al34k2 and alADA are cut by human tryptase and chymase. Interestingly, al34k2 dose-dependently enhance enzymatic activity of both tryptase and chymase. In contrast, while alADA enhances the enzymatic activity of tryptase, chymase activity was inhibited. Our finding suggests that alADA and al34k2 via interaction with mast cell-specific proteases tryptase and chymase modulate mast cell-driven immune response in the local skin microenvironment. alADA- and al34k2-mediated modulation of tryptase and chymase may also recruit more inflammatory cells and induce vascular leakage, which may contribute to the inflammatory responses at the mosquito bite site.
Topics: Adenosine Deaminase; Aedes; Animals; Chymases; Endopeptidases; Humans; Interleukin-6; Mast Cells; Mice; Peptide Hydrolases; Salivary Proteins and Peptides; Tryptases; beta-N-Acetylhexosaminidases
PubMed: 35746853
DOI: 10.1080/21655979.2022.2081652 -
International Journal of Molecular... Aug 2022Mast cells (MCs) produce a variety of mediators, including proteases-tryptase, chymase, and carboxypeptidases-which are important for the immune response. However, a...
Mast cells (MCs) produce a variety of mediators, including proteases-tryptase, chymase, and carboxypeptidases-which are important for the immune response. However, a detailed assessment of the mechanisms of biogenesis and excretion of proteases in melanoma has yet to be carried out. In this study, we present data on phenotype and secretory pathways of proteases in MCs in the course of melanoma. The development of melanoma was found to be accompanied by the appearance in the tumor-associated MC population of several pools with a predominant content of one or two specific proteases with a low content or complete absence of others. Elucidation of the molecular and morphological features of the expression of MC proteases in melanoma allows us a fresh perspective of the pathogenesis of the disease, and can be used to clarify MCs classification, the disease prognosis, and evaluate the effectiveness of ongoing antitumor therapy.
Topics: Carboxypeptidases; Chymases; Humans; Mast Cells; Melanoma; Peptide Hydrolases; Tryptases
PubMed: 36012196
DOI: 10.3390/ijms23168930 -
International Journal of Molecular... Oct 2020The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a... (Review)
Review
The development and progression of non-alcoholic steatohepatitis (NASH) are linked to oxidative stress, inflammation, and fibrosis of the liver. Chymase, a chymotrypsin-like enzyme produced in mast cells, has various enzymatic actions. These actions include activation of angiotensin II, matrix metalloproteinase (MMP)-9, and transforming growth factor (TGF)-β, which are associated with oxidative stress, inflammation, and fibrosis, respectively. Augmentation of chymase activity in the liver has been reported in various NASH models. Generation of hepatic angiotensin II and related oxidative stress is upregulated in NASH but attenuated by treatment with a chymase inhibitor. Additionally, increases in MMP-9 and accumulation of inflammatory cells are observed in NASH but are decreased by chymase inhibitor administration. TGF-β and collagen I upregulation in NASH is also attenuated by chymase inhibition. These results in experimental NASH models demonstrate that a chymase inhibitor can effectively ameliorate NASH via the reduction of oxidative stress, inflammation, and fibrosis. Thus, chymase may be a therapeutic target for amelioration of NASH.
Topics: Animals; Chymases; Enzyme Inhibitors; Humans; Liver; Non-alcoholic Fatty Liver Disease
PubMed: 33066113
DOI: 10.3390/ijms21207543