Neuroblast Differentiation-Associated Protein Derived Polypeptides: AHNAK(5758-5775) Induced Inflammatory Reaction in Skin By Mast Cells Activation

2021 ◽  
Author(s):  
Delu Che ◽  
Xiangjin Song ◽  
Lei Zhang ◽  
Xueshan Du ◽  
Yi Zheng ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Activation ◽  
Skin Inflammation ◽  
Dynamics Simulation ◽  
Mast Cell Activation ◽  
Human Neutrophils ◽  
Activation Effect ◽  
Neuroblast Differentiation

Abstract Psoriasis is a chronic inflammatory skin disease. Mast cells significantly increase and activate in the lesions and are involved in psoriatic inflammation. Neuroblast differentiation-associated protein (AHNAK) mainly express in skin, esophagus and kidney, which participates in the differentiation of neurons, the formation of cytoskeletal structure muscular regeneration and the calcium homeostasis process. Whether AHNAK is involved in mast cell activation is unclear, and the mechanisms of AHNAK induced skin inflammation also needs investigation. To investigate whether Neuroblast differentiation-associated protein derived polypeptides: AHNAK(5758-5775) activates mast cells and induces skin inflammation contributing to psoriasis, wild-type mice were treated with AHNAK(5758-5775) to observe inflammatory cells infiltrated in skin and cytokines release in vivo. Release of inflammatory mediators by mouse primary mast cells, LAD2 cells and human neutrophils were measured in vitro. Neutrophils and mast cells were co-cultured to verify AHNAK(5758-5775)’ role in inflammation. Molecular docking analysis, molecular dynamics simulation and siRNA transfection were used to prove the receptor of AHNAK(5758-5775). AHNAK(5758-5775) caused skin inflammation in WT mice by recruitment of neutrophils and cytokines release. Moreover, AHNAK(5758-5775) does not directly activate neutrophils PPD, while it is via mast cells. ST2 seems to be a key receptor meditating the activation effect of AHNAK(5758-5775) on mast cells and lead to cytokines release. Altogether, we proposed the novel polypeptide: AHNAK(5758-5775), which might induce inflammation and participated in the occurrence and development of psoriasis by activating mast cells.

scholarly journals IgE Enhances Mouse Mast Cell FcεRI Expression In Vitro and In Vivo: Evidence for a Novel Amplification Mechanism in IgE-dependent Reactions

1997 ◽  
Vol 185 (4) ◽  
pp. 663-672 ◽  
Author(s):  
Masao Yamaguchi ◽  
Chris S. Lantz ◽  
Hans C. Oettgen ◽  
Ildy M. Katona ◽  
Tony Fleming ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Specific Antigen ◽  
Mast Cell Activation ◽  
Proinflammatory Mediators ◽  
Mouse Mast Cell

The binding of immunoglobulin E (IgE) to high affinity IgE receptors (FcεRI) expressed on the surface of mast cells primes these cells to secrete, upon subsequent exposure to specific antigen, a panel of proinflammatory mediators, which includes cytokines that can also have immunoregulatory activities. This IgE- and antigen-specific mast cell activation and mediator production is thought to be critical to the pathogenesis of allergic disorders, such as anaphylaxis and asthma, and also contributes to host defense against parasites. We now report that exposure to IgE results in a striking (up to 32-fold) upregulation of surface expression of FcεRI on mouse mast cells in vitro or in vivo. Moreover, baseline levels of FcεRI expression on peritoneal mast cells from genetically IgE-deficient (IgE −/−) mice are dramatically reduced (by ∼83%) compared with those on cells from the corresponding normal mice. In vitro studies indicate that the IgE-dependent upregulation of mouse mast cell FcεRI expression has two components: an early cycloheximide-insensitive phase, followed by a later and more sustained component that is highly sensitive to inhibition by cycloheximide. In turn, IgE-dependent upregulation of FcεRI expression significantly enhances the ability of mouse mast cells to release serotonin, interleukin-6 (IL-6), and IL-4 in response to challenge with IgE and specific antigen. The demonstration that IgE-dependent enhancement of mast cell FcεRI expression permits mast cells to respond to antigen challenge with increased production of proinflammatory and immunoregulatory mediators provides new insights into both the pathogenesis of allergic diseases and the regulation of protective host responses to parasites.

scholarly journals Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

2021 ◽  
Author(s):  
Hui-Na Wang ◽  
Kunmei Ji ◽  
Li-Na Zhang ◽  
Chu-Chu Xie ◽  
Wei-Yong Li ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cells ◽  
Cell Activation ◽  
Model Systems ◽  
Mast Cell Activation ◽  
Mouse Bone Marrow ◽  
Ige Mediated ◽  
Fos Expression

Abstract Background: Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses. Methods: In vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with β-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease. Results: c-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced FcεRI-mediated MC degranulation (evidenced by β-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice.Conclusion: IgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.

scholarly journals S100A4 Is Critical for a Mouse Model of Allergic Asthma by Impacting Mast Cell Activation

2021 ◽  
Vol 12 ◽  
Author(s):  
Tongqian Wu ◽  
Lan Ma ◽  
Xiaoqian Jin ◽  
Jingjing He ◽  
Ke Chen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Calcium Binding ◽  
Cell Activation ◽  
Allergic Diseases ◽  
Lavage Fluid ◽  
Mast Cell Activation ◽  
Asthma Model

BackgroundThe calcium-binding protein S100A4 demonstrates important regulatory roles in many biological processes including tumorigenesis and inflammatory disorders such as allergy. However, the specific mechanism of the contribution of S100A4 to allergic diseases awaits further clarification.ObjectiveTo address the effect of S100A4 on the regulation of mast cell activation and its impact on allergy.MethodsBone marrow-derived cultured mast cells (BMMCs) were derived from wild-type (WT) or S100A4-/- mice for in vitro investigation. WT and S100A4-/- mice were induced to develop a passive cutaneous anaphylaxis (PCA) model, a passive systemic anaphylaxis (PSA) model, and an ovalbumin (OVA)-mediated mouse asthma model.ResultsFollowing OVA/alum-based sensitization and provocation, S100A4-/- mice demonstrated overall suppressed levels of serum anti-OVA IgE and IgG antibodies and proinflammatory cytokines in serum, bronchoalveolar lavage fluid (BALF), and lung exudates. S100A4-/- mice exhibited less severe asthma signs which included inflammatory cell infiltration in the lung tissue and BALF, and suppressed mast cell recruitment in the lungs. Reduced levels of antigen reencounter-induced splenocyte proliferation in vitro were recorded in splenocytes from OVA-sensitized and challenged mice that lacked S100A4-/-. Furthermore, deficiency in the S100A4 gene could dampen mast cell activation both in vitro and in vivo, evidenced by reduced β-hexosaminidase release and compromised PCA and PSA reaction. We also provided evidence supporting the expression of S100A4 by mast cells.ConclusionS100A4 is required for mast cell functional activation, and S100A4 may participate in the regulation of allergic responses at least partly through regulating the activation of mast cells.

scholarly journals Trigonelline, An Alkaloid From Leonurus japonicus Houtt., Suppresses Mast Cell Activation and OVA-Induced Allergic Asthma

2021 ◽  
Vol 12 ◽  
Author(s):  
Wenhui Zhang ◽  
Yingling Zhang ◽  
Simin Chen ◽  
Hong Zhang ◽  
Man Yuan ◽  
...  
Keyword(s):  
Mast Cells ◽  
Cell Activation ◽  
Immunoglobulin E ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mast Cell Activation ◽  
Dependent Manner ◽  
Anti Inflammatory

Trigonelline, one of the active compounds from Leonurus japonicus Houtt., has been proven to have pharmacological value in diabetes, the central nervous system and cardiovascular diseases. Recent studies have shown that it may also be beneficial in controlling inflammation. However, the mechanism of the antiallergic effects of trigonelline has not been well studied. As the key effector cells participating in the development of allergies, mast cells have been linked to the pathogenesis of asthma for ages. In this study, we demonstrated the inhibitory effect of trigonelline on activated bone marrow-derived mast cells (BMMCs) and verified its anti-inflammatory properties using an ovalbumin (OVA)-induced asthma model. Trigonelline suppressed BMMC degranulation and decreased the production of the cytokines, prostaglandin D2 (PGD2) and leukotriene C4 (LTC4) in a dose-dependent manner. The potent mechanism is mainly through the suppression of the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways. Trigonelline can alleviate pathological damage in lung tissue and reduce the levels of serum immunoglobulin E (IgE) and T helper 2 (Th2) cytokines. RNA-seq results revealed the HIF-1α to be a potential target for the allergic reaction. Taken together, our study demonstrated that trigonelline can inhibit allergic inflammation in vitro and in vivo, which may provide a basis for novel anti-inflammatory drug development.

Abstract 1947: Chymase Inhibition Reduces the Incidence of Intraplaque Hemorrhage and Induces a Stable Atherosclerotic Plaque Phenotype in ApoE Deficient Mice

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Ilze Bot ◽  
Marijke M Westra ◽  
Sandra H van Heiningen ◽  
Hans Hilpert ◽  
Inge M Lankhuizen ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Atherosclerotic Plaque ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Intraplaque Hemorrhage ◽  
Plaque Stability ◽  
Plaque Destabilization

Mast cells are abundantly present in perivascular tissue during atherosclerotic plaque progression and were previously demonstrated to contribute significantly to plaque destabilization. In this study, we aimed to investigate to what extent inhibition of chymase, one of the mast cell proteases, could enhance plaque stability. We demonstrated earlier that the specific chymase inhibitor RO501 (1 μM) was able to quench mast cell activation in vitro , as illustrated by a decreased β-hexosaminidase (−41% and −80%, respectively; P<0.05) as well as chymase activity in the releasate of activated MC/9 and peritoneal mast cells (−71% and −65%, respectively; P<0.05). Next, we assessed whether chymase inhibition was also effective in vivo. Atherosclerotic carotid artery lesions were induced in ApoE −/− mice by perivascular collar placement and mast cells were activated by DNP challenge systemically during lesion development. RO501 (50 mg/kg/day) was administered as diet supplement, leading to serum concentrations of ~2 μM. While plaque size after 6 weeks of treatment did not differ, collagen content of the lesions was 2-fold enhanced in mice treated with RO501 compared to controls (1.4 ± 0.5% and 0.7 ± 0.2%, respectively). This was accompanied by a significant decrease in necrotic core size of the plaques (controls: 52 ± 3% versus RO501: 41 ± 4%, P<0.05). To determine the effects of chymase inhibition after acute mast cell activation in advanced plaques, perivascular mast cells were focally activated in the adventitia of advanced lesions in ApoE −/− mice, which were treated with RO501 as described above. At three days after focal mast cell challenge, the incidence of intraplaque hemorrhage (IPH) was inhibited from 23% in control mice to 4.5% in RO501 treated mice, while also the plaque erythrocyte area was reduced by >90% from 1.2 ± 0.6*10 3 to 0.1 ± 0.08*10 3 μm 2 (P<0.05). Also, we observed a reduction in apoptotic cells (RO501: 0.68 ± 0.20% vs. 1.01 ± 0.36% for IPH negative controls and 1.23 ± 0.42% for IPH + plaques). In conclusion, our data suggest that chymase inhibition at least partly prevents the detrimental effects of perivascular mast cells on plaque stability, identifying chymase inhibition as a new therapeutic approach in the prevention of acute coronary syndromes.

scholarly journals SWAP-70 Regulates c-kit-Induced Mast Cell Activation, Cell-Cell Adhesion, and Migration

2004 ◽  
Vol 24 (23) ◽  
pp. 10277-10288 ◽  
Author(s):  
Raja Rajeswari Sivalenka ◽  
Rolf Jessberger
Keyword(s):  
Mast Cell ◽  
Cell Adhesion ◽  
Mast Cells ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Calcium Flux ◽  
Mutant Cells

ABSTRACT SWAP-70, an unusual phosphatidylinositol-3-kinase-dependent protein that interacts with the RhoGTPase Rac, is highly expressed in mast cells. Cultured bone marrow mast cells (BMMC) from SWAP-70−/− mice are reduced in FcεRI-triggered degranulation. This report describes the hitherto-unknown role of SWAP-70 in c-kit receptor signaling, a key proliferation and differentiation pathway in mast cells. Consistent with the role of Rac in cell motility and regulation of the actin cytoskeleton, mutant cells show abnormal actin rearrangements and are deficient in migration in vitro and in vivo. SWAP-70−/− BMMC are impaired in calcium flux, in proper translocation and activity of Akt kinase (required for mast cell activation and survival), and in translocation of Rac1 and Rac2 upon c-kit stimulation. Adhesion to fibronectin is reduced, but homotypic cell association induced through c-kit is strongly increased in SWAP-70−/− BMMC. Homotypic association requires extracellular Ca2+ and depends on the integrin αLβ2 (LFA-1). ERK is hyperactivated upon c-kit signaling in adherent and dispersed mutant cells. Together, we suggest that SWAP-70 is an important regulator of specific effector pathways in c-kit signaling, including mast cell activation, migration, and cell adhesion.

scholarly journals Sinomenine potentiates P815 cell degranulation via upregulation of Ca2+ mobilization through the Lyn/PLCγ/IP3R pathway

2016 ◽  
Vol 29 (4) ◽  
pp. 676-683 ◽  
Author(s):  
Nan Wang ◽  
Rui Liu ◽  
Yanping Liu ◽  
Ruirui Zhang ◽  
Langchong He
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Drug Allergy ◽  
Cell Activation ◽  
Mast Cell Activation ◽  
Enzyme Linked Immunosorbent Assay ◽  
Sinomenium Acutum ◽  
Underlying Mechanisms

Mast cells are vital mediators of drug allergy and, therefore, studying the relationship between drug allergy and mast cells is essential. Sinomenine is the principal active component of Sinomenium acutum, which has anti-inflammatory and anti-immune effects, and is used to treat various rheumatoid diseases. However, allergic responses to sinomenine are frequently reported. Therefore, this study assessed the effects of sinomenine on mast cell activation to characterize its allergic effects and the underlying mechanisms. Enzyme-linked immunosorbent assay (ELISA), western blot analyses, and degranulation assays were performed to measure pro-inflammatory and allergic mediators in P815 cells. The allergenic effects of sinomenine were also determined in mice by using active general anaphylaxis (ASA). The results indicated that sinomenine induced inositol-1,4,5-trisphosphate (IP3) production and the release of histamine, interleukin (IL)-6, and endoplasmic reticulum Ca2+ in P815 cells. Furthermore, sinomenine upregulated the phosphorylation of sarcoma (Src), phospholipase C (PLC)-γ1, and IP3 receptor (R). Therefore, sinomenine induced concentration-dependent mast cell activation directly in vitro. Furthermore, our in vivo data identified an appropriate intravenous dose that did not induce these allergic effects, thereby providing information for the potential safe clinical use of sinomenine.

scholarly journals Role of mucosal mast cells in early vascular permeability changes of intestinal DTH reaction in the rat

1998 ◽  
Vol 274 (5) ◽  
pp. G832-G839 ◽  
Author(s):  
Aletta D. Kraneveld ◽  
Thea Muis ◽  
Andries S. Koster ◽  
Frans P. Nijkamp
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Vascular Leakage ◽  
Mast Cell Activation ◽  
Mucosal Mast Cell ◽  
Mucosal Mast Cells

Previously, it was shown that depletion and stabilization of the mucosal mast cell around the time of challenge were very effective in reducing delayed-type hypersensitivity (DTH) reactions in the small intestine of the rat. The role of mucosal mast cells in the early component of intestinal DTH reaction was further investigated in this study. In vivo small intestinal vascular leakage and serum levels of rat mast cell protease II (RMCP II) were determined within 1 h after intragastric challenge of rats that had been sensitized with dinitrobenzene 5 days before. A separate group of rats was used to study vasopermeability in isolated vascularly perfused small intestine after in vitro challenge. To investigate the effects of mast cell stabilization on the early events of the DTH reaction, doxantrazole was used. The influence of sensory nerves was studied by means of neonatal capsaicin-induced depletion of sensory neuropeptides. Within 1 h after challenge, a significant increase in vascular permeability was found in vivo as well as in vitro. This was associated with a DTH-specific increase in RMCP II in the serum, indicating mucosal mast cell activation. In addition, doxantrazole treatment and caspaicin pretreatment resulted in a significant inhibition of the DTH-induced vascular leakage and an increase in serum RMCP II. These findings are consistent with an important role for mucosal mast cells in early vascular leakage changes of intestinal DTH reactions. In addition, sensory nervous control of mucosal mast cell activation early after challenge is demonstrated.

scholarly journals ORMDL2 Deficiency Potentiates the ORMDL3-Dependent Changes in Mast Cell Signaling

2021 ◽  
Vol 11 ◽  
Author(s):  
Viktor Bugajev ◽  
Ivana Halova ◽  
Livia Demkova ◽  
Sara Cernohouzova ◽  
Petra Vavrova ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Signaling ◽  
Mammalian Cells ◽  
Cell Activation ◽  
De Novo ◽  
Mast Cell Activation ◽  
Whole Body

The systemic anaphylactic reaction is a life-threatening allergic response initiated by activated mast cells. Sphingolipids are an essential player in the development and attenuation of this response. De novo synthesis of sphingolipids in mammalian cells is inhibited by the family of three ORMDL proteins (ORMDL1, 2, and 3). However, the cell and tissue-specific functions of ORMDL proteins in mast cell signaling are poorly understood. This study aimed to determine cross-talk of ORMDL2 and ORMDL3 proteins in IgE-mediated responses. To this end, we prepared mice with whole-body knockout (KO) of Ormdl2 and/or Ormdl3 genes and studied their role in mast cell-dependent activation events in vitro and in vivo. We found that the absence of ORMDL3 in bone marrow-derived mast cells (BMMCs) increased the levels of cellular sphingolipids. Such an increase was further raised by simultaneous ORMDL2 deficiency, which alone had no effect on sphingolipid levels. Cells with double ORMDL2 and ORMDL3 KO exhibited increased intracellular levels of sphingosine-1-phosphate (S1P). Furthermore, we found that concurrent ORMDL2 and ORMDL3 deficiency increased IκB-α phosphorylation, degranulation, and production of IL-4, IL-6, and TNF-α cytokines in antigen-activated mast cells. Interestingly, the chemotaxis towards antigen was increased in all mutant cell types analyzed. Experiments in vivo showed that passive cutaneous anaphylaxis (PCA), which is initiated by mast cell activation, was increased only in ORMDL2,3 double KO mice, supporting our in vitro observations with mast cells. On the other hand, ORMDL3 KO and ORMDL2,3 double KO mice showed faster recovery from passive systemic anaphylaxis, which could be mediated by increased levels of blood S1P presented in such mice. Our findings demonstrate that Ormdl2 deficiency potentiates the ORMDL3-dependent changes in mast cell signaling.

scholarly journals Inhibition of c-Fos expression attenuates IgE-mediated mast cell activation and allergic inflammation by counteracting an inhibitory AP1/Egr1/IL-4 axis

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Hui-Na Wang ◽  
Kunmei Ji ◽  
Li-Na Zhang ◽  
Chu-Chu Xie ◽  
Wei-Yong Li ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Mast Cells ◽  
Cell Activation ◽  
Model Systems ◽  
Mast Cell Activation ◽  
Mouse Bone Marrow ◽  
Ige Mediated ◽  
Fos Expression

Abstract Background Activator protein-1 (AP1), a c-Fos–JUN transcription factor complex, mediates many cytobiological processes. c-Fos has been implicated in immunoglobulin (Ig)E activation of mast cells (MCs) via high-affinity IgE Fc receptor (FcεRI) binding. This study examined c-Fos involvement in MC activation and tested the effects of the c-Fos/AP1 inhibitor T-5224 on MCs activation and allergic responses. Methods In vitro studies were conducted with two MC model systems: rat basophilic leukemia cells (RBLs) and mouse bone marrow derived mast cells (BMMCs). MC degranulation and effector functions were examined with β-hexosaminidase release and cytokine secretion assays. c-Fos/AP1 was inhibited with T-5224. c-Fos activity was suppressed with short hairpin RNA targeting c-Fos (shFos). In vivo immune responses were evaluated in passive cutaneous anaphylaxis (PCA) and ovalbumin-induced active systemic anaphylaxis (ASA) models, as well as in an oxazolone (OXA)-induced model of atopic dermatitis, a common allergic disease. Results c-Fos expression was elevated transcriptionally and translationally in IgE-stimulated MCs. c-Fos binding of the Egr1 (early growth response 1) promoter upregulated Egr1 transcription, leading to production of interleukin (IL)4. T-5224 reduced FcεRI-mediated MC degranulation (evidenced by β-hexosaminidase activity and histamine levels) and diminished EGR1 and IL4 expression. T-5224 attenuated IgE-mediated allergic responses in PCA and ASA models, and it suppressed MC-mediated atopic dermatitis in mice. Conclusion IgE binding can activate MCs via a c-Fos/Egr1/IL-4 axis. T-5224 suppresses MC activation in vitro and in vivo and thus represents a promising potential strategy for targeting MC activation to treat allergic diseases.

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