Mast cell–mediated inflammatory responses require the α2β1 integrin

Blood ◽  
2004 ◽  
Vol 103 (6) ◽  
pp. 2214-2220 ◽  
Author(s):  
Brian T. Edelson ◽  
Zhengzhi Li ◽  
Loretta K. Pappan ◽  
Mary M. Zutter
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Biology ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Neutrophil Migration ◽  
Mast Cell Activation ◽  
Integrin Subunit ◽  
Peritoneal Mast Cells ◽  
Α2β1 Integrin

Abstract Although the α2β1 integrin is widely expressed and has been extensively studied, it has not been previously implicated in mast cell biology. We observed that α2 integrin subunit-deficient mice exhibited markedly diminished neutrophil and interleukin-6 responses during Listeria monocytogenes– and zymosan-induced peritonitis. Since exudative neutrophils of wild-type mice expressed little α2β1 integrin, it seemed unlikely that this integrin mediated neutrophil migration directly. Here, we demonstrate constitutive α2β1 integrin expression on peritoneal mast cells. Although α2-null mice contain normal numbers of peritoneal mast cells, these α2-null cells do not support in vivo mast cell–dependent inflammatory responses. We conclude that α2β1 integrin provides a costimulatory function required for mast cell activation and cytokine production in response to infection.

scholarly journals Novel collectin/C1q receptor mediates mast cell activation and innate immunity

Blood ◽  
2006 ◽  
Vol 107 (1) ◽  
pp. 143-150 ◽  
Author(s):  
Brian T. Edelson ◽  
Thomas P. Stricker ◽  
Zhengzhi Li ◽  
S. Kent Dickeson ◽  
Virginia L. Shepherd ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Critical Role ◽  
Cytokine Secretion ◽  
Mast Cell Activation ◽  
Integrin Subunit ◽  
Complement Protein ◽  
Α2β1 Integrin

Abstract Mast cells play a critical role in innate immunity, allergy, and autoimmune diseases. The receptor/ligand interactions that mediate mast cell activation are poorly defined. The α2β1 integrin, a receptor for collagens, laminins, decorin, E-cadherin, matrix metalloproteinase-1 (MMP-1), endorepellin, and several viruses, has been implicated in normal developmental, inflammatory, and oncogenic processes. We recently reported that α2 integrin subunit–deficient mice exhibited markedly diminished neutrophil and IL-6 responses during Listeria monocytogenes–and zymosan-induced peritonitis. Peritoneal mast cells require α2β1 integrin expression for activation in response to pathogens, yet the ligand and molecular mechanisms by which the α2β1 integrin induces activation and cytokine secretion remain unknown. We now report that the α2β1 integrin is a novel receptor for multiple collectins and the C1q complement protein. We demonstrate that the α2β1 integrin provides a costimulatory function required for mast cell activation and cytokine secretion. This finding suggests that the α2β1 integrin is not only important for innate immunity but may serve as a critical target for the regulation of autoimmune/allergic disorders.

scholarly journals Dnmt3arestrains mast cell inflammatory responses

2017 ◽  
Vol 114 (8) ◽  
pp. E1490-E1499 ◽  
Author(s):  
Cristina Leoni ◽  
Sara Montagner ◽  
Andrea Rinaldi ◽  
Francesco Bertoni ◽  
Sara Polletti ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Mast Cell ◽  
Cell Biology ◽  
Dna Methyltransferase ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Mast Cell Activation ◽  
Cell Responses

DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations inDNMT3Acorrelate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lackingDnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence ofDnmt3awere recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation ofDnmt1expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.

Abstract 476: Mast Cell--Mediated Neutrophil Influx Enhances Plaque Progression

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Anouk Wezel ◽  
H Maxime Lagraauw ◽  
Daniël van der Velden ◽  
Saskia C de Jager ◽  
Paul H Quax ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Neutrophil Migration ◽  
Fold Increase ◽  
Mast Cell Activation ◽  
Neutrophil Influx ◽  
Migration Assay ◽  
Cell Activator

Rationale: Activated mast cells have been identified in atherosclerotic plaques. As mast cells have the ability to release chemokines that mediate leukocyte fluxes, we propose that activated mast cells play a pivotal role in leukocyte recruitment during atherosclerosis. Methods and Results: Diet fed B-cell deficient apoE-/-muChain mice, which lack endogenous IgE, received 6 IgE or PBS injections over a period of 8 weeks. Mast cells in the aortic root were significantly more activated after IgE treatment and concomitantly, we detected an increase in plaque size (P=0.050). Intriguingly, a striking increase in the amount of perivascular neutrophils was observed in IgE treated mice (control: 57.6 ± 10.6 neutrophils/mm2 tissue; IgE: 183.0 ± 38.7 neutrophils/mm2 tissue; P=0.01). In order to investigate if activated mast cells can directly attract neutrophils, we injected C57Bl/6 or mast cell deficient Kit(W-sh/W-sh) mice intra-peritoneal with the mast cell activator 48/80. Interestingly, mast cell activation led to a massive neutrophil influx into the peritoneal cavity, while neutrophil numbers in mast cell deficient mice remained unaffected. To confirm these findings, we performed an in vitro migration assay. Indeed, supernatant of activated mast cells caused a 3-fold increase in neutrophil migration (P=0.007). Moreover, addition of anti-CXCR2 to the neutrophils resulted in a major reduction of migration (P=0.03) whereas anti-CXCR4 did not reduce migration significantly. Conclusions: Chemokines released from activated perivascular mast cells induce neutrophil recruitment to the atherosclerotic plaque, thereby aggravating the inflammatory response.

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.

Abstract 471: Systemic Chymase Inhibition Directs Atherosclerotic Plaques Towards a Stable Phenotype in ApoE Deficient Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Ilze Bot ◽  
Sandra H van Heiningen ◽  
Jurgen Fingerle ◽  
Hans Hilpert ◽  
Theo van Berkel ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Control Diet ◽  
Mast Cell Activation ◽  
Human Coronary Artery ◽  
Plaque Stability ◽  
Peritoneal Mast Cells ◽  
Chymase Inhibitor

Activated mast cells have been identified at the site of rupture in human coronary artery plaques and appear to contribute considerably to plaque progression and stability. We and others have previously demonstrated that the mast cell constituents chymase and tryptase promote apoptosis of plaque cells. In this study, we aimed to investigate whether inhibition of mast cell chymase by a specific chymase inhibitor indeed has a beneficial effect on plaque stability. Preincubation of 48/80 activated MC/9 murine mast cells or freshly isolated peritoneal mast cells with chymase inhibitor RO5010226 – 000 – 004 (RO501; 1 μM) inhibited mast cell activation, as illustrated by a decreased β-hexosaminidase activity in the releasate (−41% compared to control MC/9 cells, *P=0.04, and −80% compared to control peritoneal mast cells, *P=0.02) as well as chymase release and activity (−71% and −65%, *P=0.04, respectively). Next, we addressed whether chymase inhibition also was effective in vivo. Atherosclerotic carotid artery lesions were induced in ApoE −/− mice by perivascular collar placement; during lesion development mast cells were activated by a DNP challenge once weekly for 4 weeks. Concomitantly, a subset of mice received the chymase inhibitor (50 mg/kg/day, n=14) as diet supplement, leading to continuous serum concentrations of ~2 μM or control diet (n=12). After 6 weeks, the advanced plaques were analyzed for size and stability. While plaque size did not differ, collagen content of the lesions was 2-fold enhanced in mice treated with the chymase inhibitor compared to controls (RO501: 1.4 ± 0.5% versus controls: 0.7 ± 0.2%). This was accompanied by a significant decrease in necrotic core size of the plaques (RO501: 52 ± 3% versus controls: 41 ± 4%, *P=0.04) as well as by an increased plaque cellularity (RO501: 2.6 ± 0.1*10 3 versus controls: 2.3 ± 0.1*10 3 cells/mm 2 tissue). In agreement with these data we did observe increased peritoneal leukocyte numbers in the RO501 treated mice (RO501: 4.2 ± 1.1*10 6 cells versus 2.2 ± 0.3*10 6 cells in controls, *P=0.04). In conclusion, our data suggest that chymase inhibition indeed results in enhanced plaque stability, identifying chymase inhibition as a new therapeutic approach in the prevention of acute coronary syndromes.

scholarly journals XANTATINA INHIBE LA ACTIVACIÓN DE MASTOCITOS INDUCIDA POR NEUROPÉPTIDOS PRO-INFLAMATORIOS

2016 ◽  
Vol 2 (1) ◽  
pp. 16-24
Author(s):  
Patricia M. Vargas ◽  
Elia Martino ◽  
Teresa H. Fogal ◽  
Carlos E. Tonn ◽  
Alicia B. Penissi
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Substance P ◽  
Cell Activation ◽  
Neurogenic Inflammation ◽  
Light And Electron Microscopy ◽  
Serotonin Release ◽  
Mast Cell Activation ◽  
Morphological Studies ◽  
Peritoneal Mast Cells

Los mastocitos son células del tejido conectivo que participan en la génesis y modulación de las respuestas inflamatorias. Previamente hemos demos-trado que xanthatina (xanthanólido sesquiterpeno aislado de Xanthium cavanillesii Schouw) inhibe la activación de mastocitos inducida por secretagogos experimentales. Sin embargo, se desconoce su efecto sobre la activación de mastocitos inducida por estímulos fisiopatológicos. Estos estímulos incluyen, entre otros, los neuropéptidos pro-inflamatorios sustancia P y neurotensina, responsables de una de las principales vías de inflamación neurogénica. El objetivo del presente trabajo fue estudiar el efecto de xanthatina sobre la activación de mastocitos inducida por sustancia P y neurotensina. Mastocitos peritoneales de rata se incubaron con: 1) PBS (basal); 2) sustancia P (100 µm); 3) neurotensina (50 µm); 4) xanthatina (8-320 µm)+sustancia P; 5) xanthatina (8-320 µm)+neurotensina. Se llevaron a cabo los siguientes estudios: análisis dosis-respuesta de la liberación de serotonina inducida por neuropéptidos proinflamatorios, vitalidad celular, morfología mastocitaria por microscopía óptica y electrónica, análisis de estabilidad de xanthatina por cromatografía en capa fina. Los ensayos de liberación de serotonina y los estudios morfológicos mostraron la efectividad de xanthatina para estabilizar mastocitos. El presente estudio provee la primer evidencia a favor de la hipótesis de que xanthatina inhibe la liberación de serotonina inducida por sustancia P y neurotensina a partir de mastocitos peritoneales. Este sesquiterpeno podría representar una nueva alternativa fármacológica en la regulación de la activación mastocitaria para el tratamiento de las inflamaciones neurogénicas. Mast cells are connective tissue cells involved in the genesis and modulation of inflammatory responses. We have previously shown that xanthatin (xanthanolide sesquiterpene isolated from Xanthium cavanillesii Schouw) inhibits mast cell activation induced by experimental secretagogues. However, the effect of xanthatin on mast cell activation induced by pathophysiological stimuli remains unknown. These stimuli include, among others, the pro-inflammatory neuropeptide substance P and neurotensin, responsible for one of the main pathways of neurogenic inflammation. The present study was designed to examine the effects of xanthatin on mast cell activation induced by pro-inflammatory peptides, such as substance P and neurotensin. Rat peritoneal mast cells were incubated with: 1) PBS (basal); 2) substance P (100 µm); 3) neurotensin (50 µm); 4) xanthatin (8-320 µm)+substance P; 5) xanthatin (8-320 µm)+neurotensin. Concentration-response studies of mast cell serotonin release evoked by pro-inflammatory neuropeptides, evaluation of mast cell viability and morphology by light and electron microscopy, and drug stability analysis by thin layer chromatography were performed. Serotonin release studies, carried out together with morphological studies, showed the effectiveness of xanthatin to stabilize mast cells. The present study provides the first strong evidence in favour of the hypothesis that xanthatin inhibits substance P - and neurotensin-induced serotonin release from peritoneal mast cells. Our findings may provide an insight into the design of novel pharmacological agents which may be used to regulate the mast cell response in neurogenic inflammation.

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

2008 ◽  
Vol 105 (46) ◽  
pp. 18053-18057 ◽  
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.

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

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.

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

Circulation ◽  
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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