Immune Cell Infiltration Analysis Demonstrates Excessive Mast Cell Activation in Psoriasis

Psoriasis represents multiple inflammatory processes and exaggerated physiological responses to epithelial damage by innate and adaptive immune components, thus it is critical to compare the immune cell niche in disease and healthy skin. Here, we inferred the proportions of different immune cell types in psoriatic and healthy skin using the CIBERSORT algorithm with expression profiles as input. As a result, we observed a dramatic change of immune cell profiles in psoriatic skin compared with healthy skin. Interestingly, the resting mast cells is almost eliminated in psoriatic skin. In contrast, the activated mast cells are enriched in psoriatic skin, indicating that mast cells activation may play an important role in psoriasis pathogenesis. In addition, we found that the proportion of the resting mast cells gradually come back to the normal level in lesioned skin upon etanercept treatment, suggesting that mast cells play a critical role in immune cell niche maintenance. Further experiments validated a significant decrease in mast cell population and an excessive mast cell activation in psoriatic skin compared with healthy skin. In conclusion, our integrative analyses of the immune cell profiles and the corresponding marker genes expression provide a better understanding of the inflammation response in psoriasis and important clues for clinical applications.

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

F1000Research ◽

10.12688/f1000research.8132.2 ◽

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.

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

F1000Research ◽

10.12688/f1000research.8132.1 ◽

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

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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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Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation

Infection and Immunity ◽

10.1128/iai.00290-13 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2085-2094 ◽

Cited By ~ 3

Author(s):

Elin Rönnberg ◽

Gabriela Calounova ◽

Bengt Guss ◽

Anders Lundequist ◽

Gunnar Pejler

Keyword(s):

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Serine Proteases ◽

Cell Activation ◽

Calcium Ionophore ◽

Mast Cell Activation ◽

Activated T Cells ◽

Mast Cell Protease ◽

Murine Mast Cell

ABSTRACTGranzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.

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Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

AJP Renal Physiology ◽

10.1152/ajprenal.00116.2021 ◽

2021 ◽

Author(s):

Goutham Pattabiraman ◽

Ashlee J Bell-Cohn ◽

Stephen F. Murphy ◽

Daniel J Mazur ◽

Anthony J Schaeffer ◽

...

Keyword(s):

Mast Cell ◽

Smooth Muscle ◽

Mast Cells ◽

Cell Activation ◽

Cell Function ◽

Critical Role ◽

Smooth Muscle Contraction ◽

Urinary Dysfunction ◽

Mast Cell Activation ◽

Prostate Inflammation

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells using a combination of mast cell stabilizer (MCS), cromolyn sodium, and the histamine 1 receptor antagonist (H1RA), cetirizine di-hydrochloride, in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS.

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A Practical Guide for Treatment of Pain in Patients with Systemic Mast Cell Activation Disease

January 2018 - Pain Physician ◽

10.36076/ppj.20.5.e849 ◽

2017 ◽

Vol 6 (20;6) ◽

pp. E849-E861

Author(s):

Gerhard J. Molderings

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Mast Cell Activation ◽

German Population ◽

Common Symptom ◽

Mast Cell Mediator ◽

Practical Guide ◽

Mast Cell Activation Disease ◽

High Prevalence

Systemic mast cell activation disease (MCAD, a subclass of mastocytosis), which has a prevalence of around 17% (at least in the German population), is characterized by accumulation of genetically altered dysfunctional mast cells with abnormal release of these cells’ mediators. Since mast cells affect functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing, this disease has to be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity of a generally inflammatory and allergic theme. Pain in its different manifestations is a common symptom in MCAD found in more than three-quarters of the MCAD patients. Because of the specific mast cell-related causes of pain in MCAD it should be treated specifically, if possible, deduced from their putative mast cell mediator-related causes. As yet, there is no official guideline for treatment of MCAD at all. The present review focuses on mast cell mediator-induced acute and chronic pain and the current state of analgesic drug therapy options in MCAD. Due to the high prevalence of MCAD, many physicians are often faced with the issue of pain management in MCAD patients. Hence, our practical guide should contribute to the improvement of patient care.

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The rat c-kit ligand, stem cell factor, induces c-kit receptor-dependent mouse mast cell activation in vivo. Evidence that signaling through the c-kit receptor can induce expression of cellular function.

Journal of Experimental Medicine ◽

10.1084/jem.175.1.245 ◽

1992 ◽

Vol 175 (1) ◽

pp. 245-255 ◽

Cited By ~ 88

Author(s):

B K Wershil ◽

M Tsai ◽

E N Geissler ◽

K M Zsebo ◽

S J Galli

Keyword(s):

Mast Cell ◽

Stem Cell ◽

Mast Cells ◽

Stem Cell Factor ◽

Cell Activation ◽

Mast Cell Activation ◽

Tyrosine Kinase Receptor ◽

Kit Ligand ◽

Kit Receptor

Interactions between products of the mouse W locus, which encodes the c-kit tyrosine kinase receptor, and the Sl locus, which encodes a ligand for c-kit receptor, which we have designated stem cell factor (SCF), have a critical role in the development of mast cells. Mice homozygous for mutations at either locus exhibit several phenotypic abnormalities including a virtual absence of mast cells. Moreover, the c-kit ligand SCF can induce the proliferation and maturation of normal mast cells in vitro or in vivo, and also can result in repair of the mast cell deficiency of Sl/Sld mice in vivo. We now report that administration of SCF intradermally in vivo results in dermal mast cell activation and a mast cell-dependent acute inflammatory response. This effect is c-kit receptor dependent, in that it is not observed when SCF is administered to mice containing dermal mast cells expressing functionally inactive c-kit receptors, is observed with both glycosylated and nonglycosylated forms of SCF, and occurs at doses of SCF at least 10-fold lower on a molar basis than the minimally effective dose of the classical dermal mast cell-activating agent substance P. These findings represent the first demonstration in vivo that a c-kit ligand can result in the functional activation of any cellular lineage expressing the c-kit receptor, and suggest that interactions between the c-kit receptor and its ligand may influence mast cell biology through complex effects on proliferation, maturation, and function.

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