Secretory granules of mast cells accumulate mature and immature MHC class II molecules

Bone marrow-derived mast cells as well as dendritic cells, macrophages and B lymphocytes express major histocompatibility complex (MHC) class II molecules. In mast cells, the majority of MHC class II molecules reside in intracellular cell type-specific compartments, secretory granules. To understand the molecular basis for the localisation of MHC class II molecules in secretory granules, MHC class II molecules were expressed, together with the invariant chain, in the mast cell line, RBL-2H3. Using electron and confocal microscopy, we observed that in RBL-2H3 cells, mature and immature class II molecules accumulate in secretory granules. Two particular features of class II transport accounted for this intracellular localization: first, a large fraction of newly synthesized MHC class II molecules remained associated with invariant chain fragments. This defect, resulting in a slower rate of MHC class II maturation, was ascribed to a low cathepsin S activity. Second, although a small fraction of class II dimers matured (i.e. became free of invariant chain), allowing their association with antigenic peptides, they were retained in secretory granules. As a consequence of this intracellular localization, cell surface expression of class II molecules was strongly increased by cell activation stimuli which induced the release of the contents of secretory granules. Our results suggest that antigen presentation, and thereby antigen specific T cell stimulation, are regulated in mast cells by stimuli which induce mast cell activation.

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Recent advances in mast cell activation and regulation

F1000Research ◽

10.12688/f1000research.22037.1 ◽

2020 ◽

Vol 9 ◽

pp. 196 ◽

Cited By ~ 4

Author(s):

Hwan Soo Kim ◽

Yu Kawakami ◽

Kazumi Kasakura ◽

Toshiaki Kawakami

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

De Novo ◽

Immunoglobulin E ◽

Secretory Granules ◽

Structural Features ◽

Mast Cell Activation ◽

Dependent Manner ◽

Drug Induced

Mast cells are innate immune cells that intersect with the adaptive immunity and play a crucial role in the initiation of allergic reactions and the host defense against certain parasites and venoms. When activated in an allergen- and immunoglobulin E (IgE)-dependent manner, these cells secrete a large variety of allergenic mediators that are pre-stored in secretory granules or de novo–synthesized. Traditionally, studies have predominantly focused on understanding this mechanism of mast cell activation and regulation. Along this line of study, recent studies have shed light on what structural features are required for allergens and how IgE, particularly anaphylactic IgE, is produced. However, the last few years have seen a flurry of new studies on IgE-independent mast cell activation, particularly via Mrgprb2 (mouse) and MRGPRX2 (human). These studies have greatly advanced our understanding of how mast cells exert non-histaminergic itch, pain, and drug-induced pseudoallergy by interacting with sensory neurons. Recent studies have also characterized mast cell activation and regulation by interleukin-33 (IL-33) and other cytokines and by non-coding RNAs. These newly identified mechanisms for mast cell activation and regulation will further stimulate the allergy/immunology community to develop novel therapeutic strategies for treatment of allergic and non-allergic diseases.

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Sorting of MHC class II molecules and the associated invariant chain (Ii) in polarized MDCK cells

Journal of Cell Science ◽

10.1242/jcs.110.5.597 ◽

1997 ◽

Vol 110 (5) ◽

pp. 597-609 ◽

Cited By ~ 2

Author(s):

A. Simonsen ◽

E. Stang ◽

B. Bremnes ◽

M. Roe ◽

K. Prydz ◽

...

Keyword(s):

Epithelial Cells ◽

Antigen Presentation ◽

Mhc Class Ii ◽

Mdck Cells ◽

Intracellular Localization ◽

Cytoplasmic Tail ◽

Class Ii ◽

Invariant Chain ◽

Basolateral Targeting ◽

Mhc Class Ii Molecules

Epithelial cells have been found to express MHC class II molecules in vivo and are able to perform class II-restricted antigen presentation. The precise intracellular localization of these molecules in epithelial cells has been a matter of debate. We have analyzed the polarized targeting of human MHC class II molecules and the associated invariant chain (Ii) in stably transfected MDCK cells. The class II molecules are located at the basolateral surface and in intracellular vesicles, both when expressed alone or together with Ii. Ii is located in basolateral endosomes and can internalize through the basolateral plasma membrane domain. We show that the cytoplasmic tail of Ii contains information for basolateral targeting as it is sufficient to redirect the apical protein neuraminidase (NA) to the basolateral surface. We find that the two leucine-based motifs (LI and ML) in the cytoplasmic tail of Ii are individually sufficient for endosomal sorting and basolateral targeting of Ii in MDCK cells. In addition, basolateral sorting information is located within the 10 membrane-proximal residues of the Ii cytoplasmic tail. As several different signals mediate basolateral sorting of the class II/Ii complex, a polarized distribution of these molecules may be an essential feature of antigen presentation in epithelial cells.

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Binding of Mycoplasma arthritidis-derived mitogen to human MHC class II molecules via its N terminus is modulated by invariant chain expression and its C terminus is required for T cell activation

European Journal of Immunology ◽

10.1002/1521-4141(200006)30:6<1748::aid-immu1748>3.0.co;2-j ◽

2000 ◽

Vol 30 (6) ◽

pp. 1748-1756 ◽

Cited By ~ 11

Author(s):

Marc-André Langlois ◽

Pierre Étongué-Mayer ◽

Marc Ouellette ◽

Walid Mourad

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Class Ii ◽

Invariant Chain ◽

Mycoplasma Arthritidis ◽

C Terminus ◽

N Terminus ◽

Mhc Class Ii Molecules

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Accumulation of Major Histocompatibility Complex Class II Molecules in Mast Cell Secretory Granules and Their Release upon Degranulation

Molecular Biology of the Cell ◽

10.1091/mbc.8.12.2631 ◽

1997 ◽

Vol 8 (12) ◽

pp. 2631-2645 ◽

Cited By ~ 272

Author(s):

Graça Raposo ◽

Danielle Tenza ◽

Salahedine Mecheri ◽

Roger Peronet ◽

Christian Bonnerot ◽

...

Keyword(s):

Mast Cell ◽

Major Histocompatibility Complex ◽

Mhc Class Ii ◽

Secretory Granules ◽

Class Ii ◽

Type I ◽

Type Ii ◽

Histocompatibility Complex ◽

Secretory Lysosomes ◽

Mhc Class Ii Molecules

To investigate the relationship between major histocompatibility complex (MHC) class II compartments, secretory granules, and secretory lysosomes, we analyzed the localization and fate of MHC class II molecules in mast cells. In bone marrow-derived mast cells, the bulk of MHC class II molecules is contained in two distinct compartments, with features of both lysosomal compartments and secretory granules defined by their protein content and their accessibility to endocytic tracers. Type I granules display internal membrane vesicles and are accessed by exogenous molecules after a time lag of 20 min; type II granules are reached by the endocytic tracer later and possess a serotonin-rich electron-dense core surrounded by a multivesicular domain. In these type I and type II granules, MHC class II molecules, mannose-6-phosphate receptors and lysosomal membrane proteins (lamp1 and lamp2) localize to small intralumenal vesicles. These 60–80-nm vesicles are released along with inflammatory mediators during mast cell degranulation triggered by IgE-antigen complexes. These observations emphasize the intimate connection between the endocytic and secretory pathways in cells of the hematopoietic lineage which allows regulated secretion of the contents of secretory lysosomes, including membrane proteins associated with small vesicles.

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Mast cells express tyrosine hydroxylase and store dopamine in a serglycin-dependent manner

Biological Chemistry ◽

10.1515/bc-2011-220 ◽

2012 ◽

Vol 393 (1-2) ◽

pp. 107-112 ◽

Cited By ~ 12

Author(s):

Elin Rönnberg ◽

Gabriela Calounova ◽

Gunnar Pejler

Keyword(s):

Mast Cell ◽

Tyrosine Hydroxylase ◽

Mast Cells ◽

Cell Activation ◽

Tryptophan Hydroxylase ◽

Histidine Decarboxylase ◽

Secretory Granules ◽

Mast Cell Activation ◽

Cell Maturation ◽

Dependent Manner

AbstractHere we show that mast cells contain dopamine and that mast cell activation causes dopamine depletion, indicating its presence within secretory granules. Dopamine storage increased during mast cell maturation from bone marrow precursors, and was dependent on the presence of serglycin. Moreover, the expression of tyrosine hydroxylase, the key enzyme in dopamine biosynthesis, was induced during mast cell maturation; histidine decarboxylase and tryptophan hydroxylase 1 were also induced. Mast cell activation caused a robust induction of histidine decarboxylase, but no stimulation of tyrosine hydroxylase or tryptophan hydroxylase 1 expression. The present study points toward a possible role of dopamine in mast cell function.

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Brain mast cells link the immune system to anxiety-like behavior

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0809479105 ◽

2008 ◽

Vol 105 (46) ◽

pp. 18053-18057 ◽

Cited By ~ 108

Author(s):

Katherine M. Nautiyal ◽

Ana C. Ribeiro ◽

Donald W. Pfaff ◽

Rae Silver

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Mast Cell Activation ◽

Neural Systems ◽

Loss Of Function ◽

Littermate Control ◽

Cytokines And Chemokines ◽

Function Models ◽

The Brain

Mast cells are resident in the brain and contain numerous mediators, including neurotransmitters, cytokines, and chemokines, that are released in response to a variety of natural and pharmacological triggers. The number of mast cells in the brain fluctuates with stress and various behavioral and endocrine states. These properties suggest that mast cells are poised to influence neural systems underlying behavior. Using genetic and pharmacological loss-of-function models we performed a behavioral screen for arousal responses including emotionality, locomotor, and sensory components. We found that mast cell deficient KitW−sh/W−sh (sash−/−) mice had a greater anxiety-like phenotype than WT and heterozygote littermate control animals in the open field arena and elevated plus maze. Second, we show that blockade of brain, but not peripheral, mast cell activation increased anxiety-like behavior. Taken together, the data implicate brain mast cells in the modulation of anxiety-like behavior and provide evidence for the behavioral importance of neuroimmune links.

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Association of Mast Cell Burden and TIM-3 Expression with Recalcitrant Chronic Rhinosinusitis with Nasal Polyps

Annals of Otology Rhinology & Laryngology ◽

10.1177/0003489421995038 ◽

2021 ◽

pp. 000348942199503

Author(s):

Michael A. Belsky ◽

Erica Corredera ◽

Hridesh Banerjee ◽

John Moore ◽

Li Wang ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Chronic Rhinosinusitis ◽

Nasal Polyps ◽

Cell Activation ◽

Enzymatic Digestion ◽

Sinus Surgery ◽

Mast Cell Activation ◽

Need For Treatment ◽

Inflammatory State

Objectives: Previous work showed that higher polyp mast cell load correlated with worse postoperative endoscopic appearance in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Polyp epithelial mast cells showed increased expression of T-cell/transmembrane immunoglobulin and mucin domain protein 3 (TIM-3), a receptor that promotes mast cell activation and cytokine production. In this study, CRSwNP patients were followed post-operatively to investigate whether mast cell burden or TIM-3 expression among mast cells can predict recalcitrant disease. Methods: Nasal polyp specimens were obtained via functional endoscopic sinus surgery (FESS) and separated into epithelial and stromal layers via enzymatic digestion. Mast cells and TIM-3-expressing mast cells were identified via flow cytometry. Mann-Whitney U tests and Cox proportional hazard models assessed whether mast cell burden and TIM-3 expression were associated with clinical outcomes, including earlier recurrence of polypoid edema and need for treatment with steroids. Results: Twenty-three patients with CRSwNP were studied and followed for 6 months after undergoing FESS. Higher mast cell levels were associated with earlier recurrence of polypoid edema: epithelial HR = 1.283 ( P = .02), stromal HR = 1.103 ( P = .02). Percent of mast cells expressing TIM-3 in epithelial or stromal layers was not significantly associated with earlier recurrence of polypoid edema. Mast cell burden and TIM-3+ expression were not significantly associated with need for future treatment with steroids post-FESS. Conclusions: Mast cell load in polyp epithelium and stroma may predict a more refractory postoperative course for CRSwNP patients. The role of TIM-3 in the chronic inflammatory state seen in CRSwNP remains unclear.

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Abstract 1193: Mast Cell Activation Promotes Leukocyte Recruitment And Adhesion To The Atherosclerotic Plaque

Circulation ◽

10.1161/circ.116.suppl_16.ii_242 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Ilze Bot ◽

Saskia C de Jager ◽

Alma Zernecke ◽

Christian Weber ◽

Theo J van Berkel ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Carotid Artery ◽

Atherosclerotic Plaque ◽

Cell Activation ◽

Ex Vivo ◽

Leukocyte Adhesion ◽

Leukocyte Recruitment ◽

Mast Cell Activation ◽

Labeled Leukocytes

Activated mast cells have been identified in the perivascular tissue of human coronary artery plaques. As mast cells have been described to release a whole array of chemokines including interleukin 8 (IL-8) and MIP1 α, we propose that activated mast cells play a pivotal role in leukocyte recruitment at advanced stages of atherosclerotic plaque development. Peritoneal mast cells of either C57Bl/6 or mast cell deficient Kit(W −sh /W −sh ) mice were activated by injection of compound 48/80 (1.2 mg/kg). Interestingly, mast cell activation led to a massive neutrophil influx into the peritoneal cavity at 3 hours after activation (controls: 1 ± 0.7*10 4 Gr1 + -neutrophils/ml up to 8 ± 0.2*10 4 Gr1 + neutrophils/ml at 3 hours after activation, *P<0.05), while neutrophil numbers in Kit(W −sh /W −sh ) mice were not affected by compound 48/80 administration. Moreover, increased levels of CXCR2 + Gr1 + neutrophils (t=0: 0.55 ± 0.07% versus t=3 hours: 1.00 ± 0.12%, *P<0.05) were observed after mast cell activation. Next, we investigated whether mast cell activation also translated in induced leukocyte adhesion to advanced atherosclerotic plaques. Adventitial mast cells of advanced collar aided carotid artery plaques were activated by local application of a dinitrophenyl-BSA (DNP) challenge in ApoE −/− mice. Three days later, the carotid artery segments carrying the plaques were isolated and perfused ex vivo with rhodamine labeled leukocytes, showing a dramatically increased number of adherent leukocytes after mast cell activation (49 ± 6 versus 19 ± 4 leukocytes/microscopic field for DNP versus control plaques, respectively, **P<0.001). Strikingly, antibody blockade of either the CXCR2 or VCAM-1 receptor VLA-4 on labeled leukocytes completely inhibited leukocyte adhesion to the atherosclerotic plaque (*P<0.05), while blockade of CCR1, -3 and -5 with Met-RANTES had no effect. In conclusion, our data suggest that chemokines such as IL-8 released from activated perivascular mast cells induce leukocyte recruitment and adhesion to the atherosclerotic plaque, aggravating the ongoing inflammatory response and thus effecting plaque destabilization. We propose that mast cell stabilization could be a new therapeutic approach in the prevention of acute coronary syndromes.

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Mast cell activation is not required for induction of airway hyperresponsiveness by ozone in mice

Journal of Applied Physiology ◽

10.1152/jappl.1999.86.1.202 ◽

1999 ◽

Vol 86 (1) ◽

pp. 202-210 ◽

Cited By ~ 14

Author(s):

N. Noviski ◽

J. P. Brewer ◽

W. A. Skornik ◽

S. J. Galli ◽

J. M. Drazen ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Airway Hyperresponsiveness ◽

Essential Role ◽

Cell Activation ◽

Mast Cell Degranulation ◽

Mast Cell Activation ◽

Polymorphonuclear Cell ◽

Pulmonary Parenchyma

Exposure to ambient ozone (O3) is associated with increased exacerbations of asthma. We sought to determine whether mast cell degranulation is induced by in vivo exposure to O3in mice and whether mast cells play an essential role in the development of pulmonary pathophysiological alterations induced by O3. For this we exposed mast cell-deficient WBB6F1- kitW/ kitW-v( kitW/ kitW-v) mice and the congenic normal WBB6F1(+/+) mice to air or to 1 or 3 parts/million O3for 4 h and studied them at different intervals from 4 to 72 h later. We found evidence of O3-induced cutaneous, as well as bronchial, mast cell degranulation. Polymorphonuclear cell influx into the pulmonary parenchyma was observed after exposure to 1 part/milllion O3only in mice that possessed mast cells. Airway hyperresponsiveness to intravenous methacholine measured in vivo under pentobarbital anesthesia was observed in both kitW/ kitW-vand +/+ mice after exposure to O3. Thus, although mast cells are activated in vivo by O3and participate in O3-induced polymorphonuclear cell infiltration into the pulmonary parenchyma, they do not participate detectably in the development of O3-induced airway hyperresponsiveness in mice.

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