UNIPROT:P15088 - FACTA Search

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Query: UNIPROT:P15088 (mast cell)
14,925 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Asthma is characterized by variable airflow obstruction, airway hyperresponsiveness, and airway inflammation. Mast cells have long been thought to play a central role in asthma through their ability to release proinflammatory mediators, but this role has been questioned by the lack of efficacy of antihistamines and so-called mast cell-stabilizing drugs. Recent comparisons between the immunopathology of asthma and eosinophilic bronchitis have led to the re-emergence of the mast cell as a pivotal cell in asthma. Eosinophilic bronchitis is a condition in which patients present with chronic cough, and shares many of the inflammatory features associated with asthma, but without variable airflow obstruction or airway hyperresponsiveness. The only striking pathologic difference between these conditions is that, in asthma, the airway smooth muscle is infiltrated by mast cells. This suggests that interactions between mast cells and airway smooth muscle cells are critical for the development of the disordered airway physiology in asthma.
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PMID:The re-emergence of the mast cell as a pivotal cell in asthma pathogenesis. 1568 13

Previously, we reported the immunosuppressive action of the aqueous extract of Kalanchoe pinnata (Kp) in mice. In the present study, we report on the protective effect of Kp in fatal anaphylactic shock, likewise a Th2-driven immunopathology, and the identification of its active component. Mice daily treated with oral Kp during hypersensitization with ovalbumin were all protected against death when challenged with the allergen, as compared with the 100% mortality in the untreated group. A single intraperitoneal dose 3 h prior to challenge was partially effective. Oral protection was accompanied by a reduced production of OVA-specific IgE antibodies, reduced eosinophilia, and impaired production of the IL-5, IL-10 and TNF-alpha cytokines. In vitro, Kp prevented antigen-induced mast cell degranulation and histamine release. Oral treatment with the quercitrin flavonoid isolated from Kp prevented fatal anaphylaxis in 75% of the animals. These findings indicate that oral treatment with Kp effectively downmodulates pro-anaphylactic inducing immune responses. Protection achieved with quercitrin, although not maximal, suggests that this flavonoid is a critical component of Kp extract against this extreme allergic reaction.
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PMID:Immunomodulatory pretreatment with Kalanchoe pinnata extract and its quercitrin flavonoid effectively protects mice against fatal anaphylactic shock. 1867 40

Chemokines play important regulatory roles in immunity, but their contributions to mast cell function remain poorly understood. We examined the effects of FcepsilonRI-chemokine receptor (CCR) 1 co-stimulation on receptor localization and cellular morphology of bone marrow-derived mast cells. Whereas FcepsilonRI and CCR1 co-localized at the plasma membrane in unsensitized cells, sensitization with IgE promoted internalization of CCR1 molecules. Co-stimulation of FcepsilonRI and CCR1 with antigen and macrophage inflammatory protein-1alpha was more effective than FcepsilonRI stimulation alone in causing leading edge formation, flattened morphology, membrane ruffles and ganglioside (GM1(+)) lipid mediator release. Co-stimulation resulted in phalloidin-positive cytoneme-like cellular extensions, also known as tunneling nanotubes, which originated at points of calcium accumulation. This is the first report of cytoneme formation by mast cells. To determine the importance of lipid rafts for mast cell function, the cells were cholesterol depleted. Cholesterol depletion enhanced degranulation in resting, sensitized and co-stimulated cells, but not in FcepsilonRI-cross-linked cells, and inhibited formation of filamentous actin(+) cytonemes but not GM1(+) cytonemes. Treatment with latrunculin A to sequester globular-actin abolished cytoneme formation. The cytonemes may participate in intercellular communication during allergic and inflammatory responses, and their presence in the co-stimulated mast cells suggests new roles for CCRs in immunopathology.
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PMID:Interaction between activated chemokine receptor 1 and FcepsilonRI at membrane rafts promotes communication and F-actin-rich cytoneme extensions between mast cells. 2017 38

Tryptase and chymase are mast cell (MC)-specific proteases, which influence in the activation of inflammatory cells. In this study, we quantified tryptase- or chymase-expressing MCs in the oesophaguses of Chagas patients, and searched for a correlation between those data with area of nerve fibres that expressed either PGP9.5 (pan-marker) or vasoactive intestinal polypeptide (VIP), which is a neuromediator that has anti-inflammatory activity. Samples from the oesophaguses of 14 individuals Trypanosoma cruzi-infected and from six uninfected individuals were analysed by immunohistochemistry. It was demonstrated that the number of tryptase-IR MCs in infected individuals increased when compared with controls, regardless of whether the individuals had megaoesophagus, whereas the number of chymase-IR MCs increased only in infected individuals without megaoesophagus. Negative correlations were observed between tryptase-IR MCs and the density of nerve fibres that expressed VIP or PGP 9.5-IR. The participation of chymase and tryptase in this type of immunopathology is discussed.
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PMID:Neuroimmunopathology of Trypanosoma cruzi-induced megaoesophagus: Is there a role for mast cell proteases? 2453 Jul 52

Mast cells are regarded as complex and multifunctional cells, playing a significant role in immunopathology and a substantial role in tumor angiogenesis. Angiogenesis is a complex process that is tightly regulated by various growth factors in which mast cells act directly by releasing angiogenic factors and henceforth promoting tumor growth and metastasis. The aim of this study is to evaluate the number of mast cells in tissue sections of oral squamous cell carcinoma (OSCC) in comparison with normal mucosa. A total of 40 cases (20 OSCC and 20 normal mucosa) were stained with 1% toluidine blue and the quantitative analysis was done by using light microscope under 400x magnification. A significant increase in the mast cell count was observed in the sections of OSCC when compared to normal mucosa suggesting their contributing role in tumor growth and progression.
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PMID:Incidence of mast cells in oral squamous cell carcinoma: a short study. 2458 2

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25⁺ type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.
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PMID:A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis. 2809 87

Only 2 major mast cell (MC) subtypes are commonly recognized in the mouse: the large connective tissue mast cells (CTMCs) and the mucosal mast cells (MMCs). Interepithelial mucosal inflammatory cells, most commonly identified as globule leukocytes (GLs), represent a third MC subtype in mice, which we term interepithelial mucosal mast cells (ieMMCs). This term clearly distinguishes ieMMCs from lamina proprial MMCs (lpMMCs) while clearly communicating their common MC lineage. Both lpMMCs and ieMMCs are rare in normal mouse intestinal mucosa, but increased numbers of ieMMCs are seen as part of type 2 immune responses to intestinal helminth infections and in food allergies. Interestingly, we found that increased ieMMCs were consistently associated with decreased mucosal inflammation and damage, suggesting that they might have a role in controlling helminth-induced immunopathology. We also found that ieMMC hyperplasia can develop in the absence of helminth infections, for example, in Treg-deficient mice, Arf null mice, some nude mice, and certain graft-vs-host responses. Since tuft cell hyperplasia plays a critical role in type 2 immune responses to intestinal helminths, we looked for (but did not find) any direct relationship between ieMMC and tuft cell numbers in the intestinal mucosa. Much remains to be learned about the differing functions of ieMMCs and lpMMCs in the intestinal mucosa, but an essential step in deciphering their roles in mucosal immune responses will be to apply immunohistochemistry methods to consistently and accurately identify them in tissue sections.
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PMID:Globule Leukocytes and Other Mast Cells in the Mouse Intestine. 2849 3

Cysteinyl leukotrienes (cysLTs) facilitate mucosal type 2 immunopathology by incompletely understood mechanisms. Aspirin-exacerbated respiratory disease, a severe asthma subtype, is characterized by exaggerated eosinophilic respiratory inflammation and reactions to aspirin, each involving the marked overproduction of cysLTs. Here we demonstrate that the type 2 cysLT receptor (CysLT₂R), which is not targeted by available drugs, is required in two different models to amplify eosinophilic airway inflammation via induced expression of IL-33 by lung epithelial cells. Endogenously generated cysLTs induced eosinophilia and expanded group 2 innate lymphoid cells (ILC2s) in aspirin-exacerbated respiratory disease-like Ptges^-/- mice. These responses were mitigated by deletions of either Cysltr2 or leukotriene C₄ synthase (Ltc4s). Administrations of either LTC₄ (the parent cysLT) or the selective CysLT₂R agonist N-methyl LTC₄ to allergen sensitized wild-type mice markedly boosted ILC2 expansion and IL-5/IL-13 generation in a CysLT₂R-dependent manner. Expansion of ILC2s and IL-5/IL-13 generation reflected CysLT₂R-dependent production of IL-33 by alveolar type 2 cells, which engaged in a bilateral feed-forward loop with ILC2s. Deletion of Cysltr1 blunted LTC₄-induced ILC2 expansion and eosinophilia but did not alter IL-33 induction. Pharmacological blockade of CysLT₂R prior to inhalation challenge of Ptges^-/- mice with aspirin blocked IL-33-dependent mast cell activation, mediator release, and changes in lung function. Thus, CysLT₂R signaling, IL-33-dependent ILC2 expansion, and IL-33-driven mast cell activation are necessary for induction of type 2 immunopathology and aspirin sensitivity. CysLT₂R-targeted drugs may interrupt these processes.
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PMID:Type 2 Cysteinyl Leukotriene Receptors Drive IL-33-Dependent Type 2 Immunopathology and Aspirin Sensitivity. 2928 4

Cysteinyl leukotrienes (cysLTs) facilitate eosinophilic mucosal type 2 immunopathology, especially in aspirin-exacerbated respiratory disease (AERD), by incompletely understood mechanisms. We now demonstrate that platelets, activated through the type 2 cysLT receptor (CysLT₂R), cause IL-33-dependent immunopathology through a rapidly inducible mechanism requiring the actions of high mobility box 1 (HMGB1) and the receptor for advanced glycation end products (RAGE). Leukotriene C₄ (LTC₄) induces surface HMGB1 expression by mouse platelets in a CysLT₂R-dependent manner. Blockade of RAGE and neutralization of HMGB1 prevent LTC₄-induced platelet activation. Challenges of AERD-like Ptges^-/- mice with inhaled lysine aspirin (Lys-ASA) elicit LTC₄ synthesis and cause rapid intrapulmonary recruitment of platelets with adherent granulocytes, along with platelet- and CysLT₂R-mediated increases in lung IL-33, IL-5, IL-13, and bronchoalveolar lavage fluid HMGB1. The intrapulmonary administration of exogenous LTC₄ mimics these effects. Platelet depletion, HMGB1 neutralization, and pharmacologic blockade of RAGE eliminate all manifestations of Lys-ASA challenges, including increase in IL-33, mast cell activation, and changes in airway resistance. Thus, CysLT₂R signaling on platelets prominently utilizes RAGE/HMGB1 as a link to downstream type 2 respiratory immunopathology and IL-33-dependent mast cell activation typical of AERD. Antagonists of HMGB1 or RAGE may be useful to treat AERD and other disorders associated with type 2 immunopathology.
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PMID:Cysteinyl leukotriene receptor 2 drives lung immunopathology through a platelet and high mobility box 1-dependent mechanism. 3066 9

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