scholarly journals Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 2906
Author(s):  
Hiroyuki Ogasawara ◽  
Masato Noguchi
Keyword(s):  
Mast Cells ◽  
Immunoglobulin E ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Neuromuscular Blocking ◽  
Drug Induced ◽  
Functional Studies ◽  
Inflammatory Conditions ◽  
Functional Analyses

Mast cells (MCs) act as primary effectors in inflammatory and allergic reactions by releasing intracellularly-stored inflammatory mediators in diseases. The two major pathways for MC activation are known to be immunoglobulin E (IgE)-dependent and -independent. Although IgE-dependent signaling is the main pathway to MC activation, IgE-independent pathways have also been found to serve pivotal roles in the pathophysiology of various inflammatory conditions. Recent studies have shown that human and mouse MCs express several regulatory receptors such as toll-like receptors (TLRs), CD48, C300a, and GPCRs, including mas-related GPCR-X2 (MRGPRX2). MRGPRX2 has been reported as a novel GPCR that is expressed in MCs activated by basic secretagogues, neurokinin peptides, host defense antimicrobial peptides, and small molecule compounds (e.g., neuromuscular blocking agents) and leads to MC degranulation and eicosanoids release under in vitro experimental condition. Functional analyses of MRGPRX2 and Mrgprb2 (mouse ortholog) indicate that MRGPRX2 is involved in MC hypersensitivity reactions causing neuroinflammation such as postoperative pain, type 2 inflammation, non-histaminergic itch, and drug-induced anaphylactic-like reactions. In this review, we discuss the roles in innate immunity through functional studies on MRGPRX2-mediated IgE-independent MC activation and also the therapeutic potential of MRGPRX2 inhibitors on allergic and inflammatory diseases.

Imidazolidinyl urea activates mast cells via MRGPRX2 to induce non-histaminergic allergy

2021 ◽  
Author(s):  
Jiapan Gao ◽  
Delu Che ◽  
Xueshan Du ◽  
Yi Zheng ◽  
Huiling Jing ◽  
...  
Keyword(s):  
Contact Dermatitis ◽  
Mast Cells ◽  
Pharmaceutical Products ◽  
Drug Induced ◽  
Inflammatory Infiltration ◽  
Local Inflammatory Response ◽  
Allergic Contact ◽  
G Protein Coupled

Abstract Imidazolidinyl urea (IU) is used as an antimicrobial preservative in cosmetic and pharmaceutical products. IU induces allergic contact dermatitis, however, the mechanism has not yet been elucidated. Mas-related G protein-coupled receptor-X2 (MRGPRX2) triggers drug-induced pseudo-allergic reactions. The aims of this study were to determine whether IU activated mast cells through MRGPRX2 to further trigger contact dermatitis. Wild-type (WT) and KitW-sh/HNihrJaeBsmJNju (MUT) mice were treated with IU to observe its effects on local inflammation and mast cells degranulation in vivo. Laboratory of allergic disease 2 cells were used to detect calcium mobilization and release of inflammatory mediators in vitro. WT mice showed a severe local inflammatory response and contact dermatitis, whereas only slight inflammatory infiltration was observed in MUT mice. Thus, MRGPRX2 mediated the IU-induced activation of mast cells. However, histamine, a typical allergen, was not involved in this process. Tryptase expressed by mast cells was the major non-histaminergic inflammatory mediator of contact dermatitis. IU induced anaphylactic reaction via MRGPRX2 and further triggering non-histaminergic contact dermatitis, which explained why antihistamines are clinically ineffective against some chronic dermatitis.

scholarly journals The transcriptional program, functional heterogeneity, and clinical targeting of mast cells

2017 ◽  
Vol 214 (9) ◽  
pp. 2491-2506 ◽  
Author(s):  
Gökhan Cildir ◽  
Harshita Pant ◽  
Angel F. Lopez ◽  
Vinay Tergaonkar
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Immunoglobulin E ◽  
Inflammatory Diseases ◽  
Small Population ◽  
Transcriptional Program ◽  
Cell Functions ◽  
New Concepts ◽  
Health And Disease ◽  
Ige Mediated

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen–immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases.

HMGB1 has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer.

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Sterile Inflammation ◽  
Clinical Testing ◽  
Specific Function ◽  
Redox States ◽  
Fundamental Knowledge

HMGB1, the second most prevalent protein inside the nucleus after histone, has sparked a lot of attention as a model DAMP molecule involved in inflammation, inflammatory diseases, and cancer. Building on the fundamental knowledge of HMGB1 as a cytokine/chemoattractant, several in vivo and in vitro studies have indicated therapeutic potential for targeting HMGB1 and lowering tissue damage once inflammation has gone awry. A few hurdles must be cleared before HMGB1 treatment may progress further into clinical trials. The exact mechanism by which HMGB1 travels from the nucleus to the cytoplasm and then to the ECM is unclear. Different HMGB1 redox states can generate in situ modulations, making it difficult to determine the specific function of HMGB1 isoforms. Furthermore, the investigation of HMGB1 and its antagonists in disease situations is complicated by various HMGB1 receptors with various degrees of cell selectivity for a certain HMGB1 isoform or HMGB1 cofactor complex. HMGB1 targeting has been found to be beneficial in the treatment of inflammation and inflammatory diseases, notably in sepsis, sterile inflammation, autoimmune diseases, and cancer, despite the difficulties. Continued HMGB1 research might help fill in the gaps in knowledge and push HMGB1 antagonists closer to the next step of clinical testing.

scholarly journals Hispidulin Inhibits Mast Cell-Mediated Allergic Inflammation through Down-Regulation of Histamine Release and Inflammatory Cytokines

Molecules ◽  
2019 ◽  
Vol 24 (11) ◽  
pp. 2131 ◽  
Author(s):  
Dong Eun Kim ◽  
Kyoung-jin Min ◽  
Min-Jong Kim ◽  
Sang-Hyun Kim ◽  
Taeg Kyu Kwon
Keyword(s):  
Mast Cells ◽  
Inflammatory Cytokines ◽  
Immunoglobulin E ◽  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Interleukin 4 ◽  
Type I ◽  
Ige Mediated ◽  
Factor Α ◽  
Jnk Activation

Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a natural compound derived from traditional Chinese medicinal herbs, and it is known to have an anti-inflammatory effect. Here, we investigated the effect of hispidulin on the immunoglobulin E (IgE)-mediated allergic responses in rat basophilic leukemia (RBL)-2H3 mast cells. When RBL-2H3 cells were sensitized with anti-dinitrophenyl (anti-DNP) IgE and subsequently stimulated with DNP-human serum albumin (HSA), histamine and β-hexosaminidase were released from the cells by degranulation of activated mast cells. However, pretreatment with hispidulin before the stimulation of DNP-HSA markedly attenuated release of both in anti-DNP IgE-sensitized cells. Furthermore, we investigated whether hispidulin inhibits anti-DNP IgE and DNP-HSA-induced passive cutaneous anaphylaxis (PCA), as an animal model for Type I allergies. Hispidulin markedly decreased the PCA reaction and allergic edema of ears in mice. In addition, activated RBL-2H3 cells induced the expression of inflammatory cytokines (tumor necrosis factor-α and interleukin-4), which are critical for the pathogenesis of allergic disease, through the activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK activation by hispidulin treatment reduced the induction of cytokine expression in the activated mast cells. Our results indicate that hispidulin might be a possible therapeutic candidate for allergic inflammatory diseases through the suppression of degranulation and inflammatory cytokines expression.

scholarly journals Bacterial Immunoglobulin Superantigen Proteins A and L Activate Human Heart Mast Cells by Interacting with Immunoglobulin E

2000 ◽  
Vol 68 (10) ◽  
pp. 5517-5524 ◽  
Author(s):  
Arturo Genovese ◽  
Jean-Pierre Bouvet ◽  
Giovanni Florio ◽  
Bärbel Lamparter-Schummert ◽  
Lars Björck ◽  
...  
Keyword(s):  
Mast Cells ◽  
Human Heart ◽  
Immunoglobulin E ◽  
Protein A ◽  
Surface Protein ◽  
Heart Tissue ◽  
Protein L ◽  
Cysteinyl Leukotriene ◽  
Proinflammatory Mediators

ABSTRACT Human heart mast cells (HHMC) have been identified in heart tissue, perivascularly, and in the intima of coronary arteries. In vitro activation of isolated HHMC induces the release of vasoactive and proinflammatory mediators (histamine, tryptase, and cysteinyl leukotriene C4 [LTC4]). We investigated the effects of several bacterial proteins on HHMC activation in vitro. HHMC released histamine, tryptase, and LTC4 in response toStaphylococcus aureus Cowan 1 and the immunoglobulin (Ig)-binding protein A, but not to S. aureus Wood 46, which does not synthesize protein A. The effect of protein A was inhibited by preincubation with monoclonal IgM VH3+. Some strains of Peptostreptococcus magnus express an Ig light chain-binding surface protein called protein L. Such bacteria and soluble protein L stimulated the release of preformed and newly synthesized mediators from HHMC. Preincubation of HHMC with either protein A or protein L resulted in complete cross-desensitization to a subsequent challenge with the heterologous stimulus or anti-IgE. Monoclonal IgE (κ chains) blocked protein L-induced release, whereas IgE (λ chains) had no effect. Streptococcal protein G, formyl-containing tripeptide, and pepstatin A did not activate HHMC. Bacterial products protein A and protein L and intact bacteria (S. aureus and P. magnus) activate HHMC by acting as Ig superantigens.

scholarly journals In Vitro and In Vivo Immunomodulator Activities of Allium sativum L.

2018 ◽  
Vol 2018 ◽  
pp. 1-10 ◽  
Author(s):  
Mouna Moutia ◽  
Norddine Habti ◽  
Abdallah Badou
Keyword(s):  
Immune Cells ◽  
Allium Sativum ◽  
Therapeutic Potential ◽  
Inflammatory Diseases ◽  
Biological Activities ◽  
Antioxidant Properties ◽  
Allergic Airway Inflammation ◽  
Cytokine Gene Expression

Allium Sativum L. (garlic), which is a species of the onion family, Alliaceae, is one of the most used plants in traditional medicine worldwide. More than 200 chemicals with diverse properties have been found in garlic extracts. Several garlic compounds were suggested to be efficient in improving various pathologies including certain types of cancer. This paper is an overview of data about garlic biological activities in vitro and/or in vivo on immune cells, on the development of certain inflammatory diseases, and on different types of carcinomas and sarcomas. Garlic and its compounds were found to have notable antioxidant properties. Garlic therapeutic potential has also been studied in several inflammatory diseases such as allergic-airway inflammation, inflammatory bowel disease, arthritic rheumatism, and atherosclerosis. Furthermore, garlic was found to be able to maintain the immune system homeostasis and to exhibit beneficial effects on immune cells especially through regulation of proliferation and cytokine gene expression. Finally, we will show how major garlic components such as sulfur compounds and polyphenols might be responsible for the garlic biological activities revealed in different situations. If identified, specific compounds present in garlic could potentially be used in therapy.

scholarly journals An immunologically anomalous but considerably bioactive GH produced by a novel GH1 mutation (p.D116E)

2009 ◽  
Vol 161 (2) ◽  
pp. 301-306 ◽  
Author(s):  
Sumito Dateki ◽  
Kazuko Hizukuri ◽  
Toshiaki Tanaka ◽  
Noriyuki Katsumata ◽  
Paravee Katavetin ◽  
...  
Keyword(s):  
Rare Condition ◽  
Normal Range ◽  
Functional Studies ◽  
Provocation Tests ◽  
Old Japanese ◽  
Igf Binding ◽  
Functional Analyses ◽  
Igf Binding Protein

ContexAlthough GH values measured by an immunoassay usually reflect GH bioactivities, discrepancy exists between immunoactivity and bioactivity in a rare condition known as ‘bioinactive GH’.ObjectiveTo report an immunologically anomalous but considerably bioactive GH.MethodsWe performed mutational and functional analyses of GH1 in a 7-year-old Japanese boy with short stature (−3.0 s.d.) in whom serum GH values measured with a Tosoh immunoassay kit were all undetectable in three provocation tests, whereas urine GH value measured with a Hitachi immunoassay kit was within the normal range. Serum IGF-1 was at a low-normal range, and IGF-binding protein-3 was below the normal range.ResultsMutation analysis showed a missense GH produced by a novel GH1 mutation (p.D116E) of paternal origin and a frameshift mutation (p.Q68fsX106) of maternal origin. Genotype–phenotype correlations in this family and in vitro functional studies indicated that the p.D116E-GH was immeasurable with the Tosoh kit but was measurable, though maybe not precise, with a Daiichi kit, and had a reduced in vivo bioactivity. The p.Q68fsX106 yielded no GH protein.ConclusionsThe results suggest that the p.D116E affects the GH epitope primarily recognized by the Tosoh kit but not by the Hitachi or the Daiichi kits, thereby producing an immunologically anomalous but considerably bioactive GH. The presence of such a hormone discordant for immunoactivity and bioactivity should be kept in mind, to allow for an appropriate assessment of endocrine data.

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 MiR-142-3p Overexpression Increases Chemo-Sensitivity of NSCLC by Inhibiting HMGB1-Mediated Autophagy

2017 ◽  
Vol 41 (4) ◽  
pp. 1370-1382 ◽  
Author(s):  
Yuqing Chen ◽  
Xin Zhou ◽  
Jianou Qiao ◽  
Aihua Bao
Keyword(s):  
Drug Resistance ◽  
Therapeutic Potential ◽  
High Mobility ◽  
In Silico Analysis ◽  
Luciferase Reporter ◽  
Hmgb1 Protein ◽  
Drug Induced ◽  
Hmgb1 Expression

Background: Non-small-cell lung cancer (NSCLC) is a deadly cancer with high mortality rate. Drug resistance represents a main obstacle in NSCLC treatment. High mobility group box-1 (HMGB1) protein promotes drug resistance in NSCLC cells by activating protective autophagy. Methods: In the current study, we investigated the regulatory role of microRNA-142-3p (miR-142-3p) in HMGB1-mediated autophagy of NSCLC cells and its impact on drug resistance of NSCLC in vitro and in vivo. HMGB1 was identified as a putative target gene of miR-142-3p by in silico analysis. Our luciferase reporter assay results confirmed that miR-142-3p directly targets the 3’-UTR of HMGB1 in NSCLC cells. Results: MiR-142-3p overexpression suppressed while miR-142-3p knockdown increased HMGB1 mRNA and protein expression. Starvation induced HMGB1 expression and activated autophagy in NSCLC cells. The starvation-induced autophagy was inhibited by miR-142-3p overexpression or HMGB1 knockdown. Moreover, miR-142-3p overexpression or HMGB1 knockdown increased PI3K, Akt, and mTOR phosphorylation. Inhibition of PI3K or mTOR restored starvation-induced autophagy inhibited by miR-142-3p overexpression or HMGB1 knockdown. Conclusions: These results demonstrated that miR-142-3p regulates starvation-induced autophagy of NSCLC cells by directly downregulating HMGB1 and subsequently activating the PI3K/Akt/mTOR pathway. Further, miR-142-3p overexpression inhibited anticancer drug-induced autophagy and increased chemo-sensitivity of NSCLC in vitro and in vivo. These findings shed light on the therapeutic potential of miR-142-3p in combating acquired NSCLC chemo-resistance.

Aqueous Extract of Mosla chinensis Inhibits Mast Cell-Mediated Allergic Inflammation

2012 ◽  
Vol 40 (06) ◽  
pp. 1257-1270 ◽  
Author(s):  
Hui-Hun Kim ◽  
Jin-Su Yoo ◽  
Tae-Yong Shin ◽  
Sang-Hyun Kim
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Histamine Release ◽  
Aqueous Extract ◽  
Proinflammatory Cytokines ◽  
Immunoglobulin E ◽  
Inflammatory Diseases ◽  
Allergic Inflammation ◽  
Inhibitory Effect ◽  
Ige Mediated

Allergic inflammatory diseases such as food allergy, asthma, sinusitis, and atopic dermatitis are increasing worldwide. In this study, we investigated the effects of aqueous extract of Mosla chinensis Max. (AMC) on mast cell-mediated allergic inflammation and studied the possible mechanism of this action. AMC inhibited compound 48/80-induced systemic and immunoglobulin E (IgE)-mediated local anaphylaxis. AMC reduced intracellular calcium levels and downstream histamine release from rat peritoneal mast cells activated by compound 48/80 or IgE. In addition, AMC decreased gene expression and secretion of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-8 in human mast cells. The inhibitory effect of AMC on cytokine expression was nuclear factor (NF)-κB dependent. Our results indicate that AMC inhibits mast cell-mediated allergic inflammatory reaction by suppressing histamine release and expression of proinflammatory cytokines and the involvement of calcium and NF-κB in these effects. AMC might be a possible therapeutic candidate for allergic inflammatory disorders.

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