scholarly journals Rno-miR-199a-3p targets Nedd4 to promote sensitization of ST36 acupoints via mast cell activation in a rat model of knee osteoarthritis

2021 ◽  
Author(s):  
Wenchuan Qi ◽  
Baitong Liu ◽  
Yilu Jiang ◽  
Xinye Luo ◽  
Zhiwei Li ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Knee Osteoarthritis ◽  
Histamine Release ◽  
Rat Model ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Ectopic Expression ◽  
The Body ◽  
Mast Cell Activation

Abstract Selecting routine points on related meridians is widely accepted as the foundational principle of acupuncture. When the body is suffering disease or injury, corresponding acupoints are thought to be activated and manifest in several sensitized forms. Sensitized acupoints hold high clinical value as a reflection of disease activity on the body surface. Mast cells have been implicated in the process of acupoint sensitization but the underlying regulatory mechanisms remain unclear. In the present study, we evaluated ST36 as a sensitized acupoint in the monosodium iodoacetate-induced knee osteoarthritis rat model. We first confirmed sensitization at the ST36 acupoint through decreases in the acupoint mechanical pain threshold and instructively found an accompanying increase in skin mast cell degranulation. Thereafter, we used highthroughput RNA sequencing to reveal potential molecular mechanisms of acupoint sensitization. We showed that rno-miR-199a-3p was highly expressed in the sensitized ST36 acupoint and its expression was associated with mast cells. Functional experiments revealed that overexpression of rno-miR-199a-3p increased mast cell histamine release whereas inhibition of rno-miR-199a-3p decreased histamine release. Mechanistically, we established rno-miR-199a-3p acted to inhibit neural precursor cell expressed developmentally down-regulated 4 (Nedd4) protein expression through miRNA-mediated targeting of the 3’-UTR of Nedd4 mRNA. Moreover, we found ectopic expression of Nedd4 antagonized histamine release in mast cells and blocked the actions of rno-miR-199a-3p overexpression. Thus, our study establishes that mast cells participate in the process of acupoint sensitization, and further reveals a novel miRNA-based mechanism which is crucial for further understanding of acupoint sensitization and acupuncture applications.

Mast cells

1997 ◽  
Vol 77 (4) ◽  
pp. 1033-1079 ◽  
Author(s):  
D. D. Metcalfe ◽  
D. Baram ◽  
Y. A. Mekori
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Tissue Repair ◽  
Defense Mechanisms ◽  
Cell Activation ◽  
Allergic Inflammation ◽  
Local Environment ◽  
The Body ◽  
Mast Cell Activation ◽  
Biological Functions

Mast cells are found resident in tissues throughout the body, particularly in association with structures such as blood vessels and nerves, and in proximity to surfaces that interface the external environment. Mast cells are bone marrow-derived and particularly depend upon stem cell factor for their survival. Mast cells express a variety of phenotypic features within tissues as determined by the local environment. Withdrawal of required growth factors results in mast cell apoptosis. Mast cells appear to be highly engineered cells with multiple critical biological functions. They may be activated by a number of stimuli that are both Fc epsilon RI dependent and Fc epsilon RI independent. Activation through various receptors leads to distinct signaling pathways. After activation, mast cells may immediately extrude granule-associated mediators and generate lipid-derived substances that induce immediate allergic inflammation. Mast cell activation may also be followed by the synthesis of chemokines and cytokines. Cytokine and chemokine secretion, which occurs hours later, may contribute to chronic inflammation. Biological functions of mast cells appear to include a role in innate immunity, involvement in host defense mechanisms against parasitic infestations, immunomodulation of the immune system, and tissue repair and angiogenesis.

scholarly journals Molecular Mechanisms of Mast Cell Activation by Cholesterol-Dependent Cytolysins

2021 ◽  
Vol 12 ◽  
Author(s):  
Lubica Draberova ◽  
Magda Tumova ◽  
Petr Draber
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Inflammatory Mediators ◽  
Pore Formation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Biologically Active ◽  
Mast Cell Activation ◽  
Concentration Changes

Mast cells are potent immune sensors of the tissue microenvironment. Within seconds of activation, they release various preformed biologically active products and initiate the process of de novo synthesis of cytokines, chemokines, and other inflammatory mediators. This process is regulated at multiple levels. Besides the extensively studied IgE and IgG receptors, toll-like receptors, MRGPR, and other protein receptor signaling pathways, there is a critical activation pathway based on cholesterol-dependent, pore-forming cytolytic exotoxins produced by Gram-positive bacterial pathogens. This pathway is initiated by binding the exotoxins to the cholesterol-rich membrane, followed by their dimerization, multimerization, pre-pore formation, and pore formation. At low sublytic concentrations, the exotoxins induce mast cell activation, including degranulation, intracellular calcium concentration changes, and transcriptional activation, resulting in production of cytokines and other inflammatory mediators. Higher toxin concentrations lead to cell death. Similar activation events are observed when mast cells are exposed to sublytic concentrations of saponins or some other compounds interfering with the membrane integrity. We review the molecular mechanisms of mast cell activation by pore-forming bacterial exotoxins, and other compounds inducing cholesterol-dependent plasma membrane perturbations. We discuss the importance of these signaling pathways in innate and acquired immunity.

Abstract 15720: Transmembrane Stem Cell Factor Delivered in Nanocarriers Promotes Angiogenesis in Ischemia Without Mast Cell Activation

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Eri Takematsu ◽  
Sanjana Srinath ◽  
Michael Sherman ◽  
Andrew K Dunn ◽  
Aaron Baker
Keyword(s):  
Mast Cell ◽  
Stem Cell ◽  
Mast Cells ◽  
Stem Cell Factor ◽  
Cell Activation ◽  
The Body ◽  
Mast Cell Activation ◽  
Protein Therapy ◽  
Current Standard ◽  
Therapeutic Benefits

Introduction: The current standard cares for peripheral artery disease (PAD) include surgical revascularizations with bypass grafting or percutaneous interventions. However, these interventions cannot be performed in a significant portion of patients, and many do not respond to these surgical procedures. Protein therapy to stimulate the body to create new vasculature is another alternative, which is minimally invasive to patients. Stem cell factor (SCF) is a candidate protein for treating PAD, but clinical use of SCF has been limited due to toxicity related to mast cell activation. SCF also exists in a transmembrane form (tmSCF), possessing differential activities from soluble SCF and has not been explored as a therapeutic agent. Results: To develop tmSCF as a therapeutic we created tmSCF embedded in liposome or lipid nanodisc (Fig. A) . Hindlimb ischemia model on WT and ob/ob mice showed that tmSCF proteliposome (tmSCFPL) and nanodisc (tmSCFND) improved blood flow recovery significantly more than control (Fig. B, C) . Mouse model of anaphylaxis revealed that tmSCF-based therapies did not activate mast cells (Fig. D, E) . Colocalization assay of c-Kit and clathrin/caveolin revealed that mast cells preferentially use clathrin-mediated pathways to internalize SCF and caveolin-mediated pathways for tmSCF-based therapies (Fig. F, G) . Surface c-Kit internalization study on mast cells showed faster uptake of SCF in comparison to tmSCF-based therapies (Fig. H) . Previous study indicates that clathrin-mediated internalization causes increased activation of mast cells. Our studies together with the previous finding suggest that mast cell activation does not occur for tmSCF-based therapies because of the slower uptake, greater utilization of the caveolin internalization pathway and weaker activation of mast cells. Conclusions: TmSCF-based therapies can provide therapeutic benefits without off-target effects on mast cells by tuning activation with nanocarriers.

Mechanisms of Nonimmunological Histamine and Tryptase Release from Human Cutaneous Mast Cells

2000 ◽  
Vol 92 (4) ◽  
pp. 1074-1081 ◽  
Author(s):  
Mette Veien ◽  
Fania Szlam ◽  
Jeannine T. Holden ◽  
Koji Yamaguchi ◽  
Donald D. Denson ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Phospholipase A2 ◽  
Histamine Release ◽  
Phospholipase C ◽  
Cell Activation ◽  
Calcium Ionophore ◽  
Calcium Ionophore A23187 ◽  
Mast Cell Activation ◽  
Ionophore A23187

Background If mast cells are stimulated they release multiple mediators that delineate markers for immunologic and nonimmunologic reactions; histamine and tryptase are the two best known. Although histamine can be assayed in plasma, it is a nonspecific marker with a very short half-life. Tryptase has a longer half-life, but its release has not been proven to be specific for anaphylaxis. The authors investigated the mechanisms of nonimmunologic histamine release from human cutaneous mast cells to understand the mechanisms of mediator release and to determine whether tryptase was specific for allergic mediated activation. Methods Dispersed mast cell suspensions isolated from neonatal foreskins underwent challenge with vancomycin, calcium ionophore A23187, morphine, and atracurium, and histamine tryptase release was measured. The effects of calcium and magnesium, along with phospholipase C and phospholipase A2 inhibitors, also were investigated. Results Tryptase and histamine both were released by the known nonimmunologic stimuli (pharmacologic agents used in the current study; r2 = 0.6). Furthermore, vancomycin- and atracurium-induced histamine release was calcium dependent. Phospholipase C and phospholipase A2 inhibitors decreased vancomycin-induced histamine release, but not calcium ionophore A23187-induced release. Conclusions Tryptase is not a specific marker of mast cell activation (ie., anaphylaxis), and signaling mechanisms for mast cell activation involve activation of phospholipase C and phospholipase A2 pathways that are also involved in other cellular activation mechanisms.

scholarly journals Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 251
Author(s):  
Binh Phong ◽  
Lawrence P. Kane
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

scholarly journals Mast cell activation is enhanced by Tim1:Tim4 interaction but not by Tim-1 antibodies

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 251
Author(s):  
Binh Phong ◽  
Lawrence P. Kane
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Immune Cell ◽  
Allergic Diseases ◽  
Mast Cell Activation ◽  
High Affinity Ige Receptor

Polymorphisms in theT cell (or transmembrane) immunoglobulin and mucin domain 1(TIM-1) gene, particularly in the mucin domain, have been associated with atopy and allergic diseases in mice and human. Genetic- and antibody-mediated studies revealed that Tim-1 functions as a positive regulator of Th2 responses, while certain antibodies to Tim-1 can exacerbate or reduce allergic lung inflammation. Tim-1 can also positively regulate the function of B cells, NKT cells, dendritic cells and mast cells. However, the precise molecular mechanisms by which Tim-1 modulates immune cell function are currently unknown. In this study, we have focused on defining Tim-1-mediated signaling pathways that enhance mast cell activation through the high affinity IgE receptor (FceRI). Using a Tim-1 mouse model lacking the mucin domain (Tim-1Dmucin), we show for the first time that the polymorphic Tim-1 mucin region is dispensable for normal mast cell activation. We further show that Tim-4 cross-linking of Tim-1 enhances select signaling pathways downstream of FceRI in mast cells, including mTOR-dependent signaling, leading to increased cytokine production but without affecting degranulation.

scholarly journals Intestinal Mucosal Mast Cells: Key Modulators of Barrier Function and Homeostasis

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 135 ◽  
Author(s):  
Mercé Albert-Bayo ◽  
Irene Paracuellos ◽  
Ana M. González-Castro ◽  
Amanda Rodríguez-Urrutia ◽  
María J. Rodríguez-Lagunas ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Cell Activity ◽  
Intestinal Barrier ◽  
The Body ◽  
Mast Cell Activation ◽  
Mucosal Barrier ◽  
Mucosal Mast Cell

The gastrointestinal tract harbours the largest population of mast cells in the body; this highly specialised leukocyte cell type is able to adapt its phenotype and function to the microenvironment in which it resides. Mast cells react to external and internal stimuli thanks to the variety of receptors they express, and carry out effector and regulatory tasks by means of the mediators of different natures they produce. Mast cells are fundamental elements of the intestinal barrier as they regulate epithelial function and integrity, modulate both innate and adaptive mucosal immunity, and maintain neuro-immune interactions, which are key to functioning of the gut. Disruption of the intestinal barrier is associated with increased passage of luminal antigens into the mucosa, which further facilitates mucosal mast cell activation, inflammatory responses, and altered mast cell–enteric nerve interaction. Despite intensive research showing gut dysfunction to be associated with increased intestinal permeability and mucosal mast cell activation, the specific mechanisms linking mast cell activity with altered intestinal barrier in human disease remain unclear. This review describes the role played by mast cells in control of the intestinal mucosal barrier and their contribution to digestive diseases.

scholarly journals Mast Cell Activation Disorders

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 124
Author(s):  
Arianna Giannetti ◽  
Emanuele Filice ◽  
Carlo Caffarelli ◽  
Giampaolo Ricci ◽  
Andrea Pession
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Clinical Manifestations ◽  
The Body ◽  
Mast Cell Activation ◽  
Detailed Knowledge ◽  
Pediatric Age ◽  
Mast Cell Activation Syndrome ◽  
Activation Syndrome

Background and Objectives: Mast cell disorders comprise a wide spectrum of syndromes caused by mast cells’ degranulation with acute or chronic clinical manifestations. Materials and Methods: In this review article we reviewed the latest findings in scientific papers about mast cell disorders with a particular focus on mast cell activation syndrome and mastocytosis in pediatric age. Results: Patients with mast cell activation syndrome have a normal number of mast cells that are hyperreactive upon stimulation of various triggers. We tried to emphasize the diagnostic criteria, differential diagnosis, and therapeutic strategies. Another primary mast cell disorder is mastocytosis, a condition with a long-known disease, in which patients have an increased number of mast cells that accumulate in different regions of the body with different clinical evolution in pediatric age. Conclusions: Mast cell activation syndrome overlaps with different clinical entities. No consensus was found on biomarkers and no clearly resolutive treatment is available. Therefore, a more detailed knowledge of this syndrome is of fundamental importance for a correct diagnosis and effective therapy.

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