Inhibition Of Mast Cell Activation Research Articles

Translational Selenium Nanoparticles to Attenuate Allergic Dermatitis through Nrf2-Keap1-Driven Activation of Selenoproteins.

Easy recurrence and strong treatment side effects significantly limit the clinical treatment of allergic dermatitis. The human trace element selenium (Se) plays essential roles in redox regulation through incorporation into selenoproteins in the form of 21st necessary amino acid selenocysteine, to participates in the pathogenesis and intervention of chronic inflammatory diseases. Therefore, based on the safe and elemental properties of Se, we construct a facile-synthesis strategy for antiallergic selenium nanoparticles (LET-SeNPs), and scale up the production by employing a spray drying method with lactose (Lac-LET-SeNPs) or maltodextrin (Mal-LET-SeNPs) as encapsulation agents realizing larger scale production and a longer storage time. As expected, these as-prepared LET-SeNPs could effectively activate the Nrf2-Keap1 signaling pathway to enhance the expression of antioxidative selenoprotein at mRNA and protein levels, then inhibit mast cell activation to achieve efficient antiallergic activity. Interestingly, LET-SeNPs undergo metabolism to seleno-amino acids to promote biosynthesis of selenoproteins, which could suppress ROS-induced cyclooxygenase-2 (COX-2) and MAPKs activation to suppress the release of histamine and inflammatory cytokines. Allergic mouse and Macaca fascicularis models further confirm that LET-SeNPs could increase the Se content and selenoprotein expression in the skin, decrease mast cells activation and inflammatory cells infiltration, and finally exhibit the high therapeutic effects on allergic dermatitis. Taken together, this study not only constructs facile large-scale synthesis of translational Se nanomedicine to break through the bottleneck problem of nanomaterials but also sheds light on its application in the intervention and treatment of allergies.

CKBA suppresses mast cell activation via ERK signaling pathway in murine atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-β-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.

Fisetin alleviates chronic urticaria by inhibiting mast cell activation via MRGPRX2.

The activation of mast cell (MC) plays an important part in the pathogenesis of chronic urticaria (CU), and the expression of MRGPRX2 (Mas-related G-protein coupled receptor X2) and the circulating levels of SP (substance P) in skin MC of CU patients increased. Fisetin is a natural flavonoid with anti-inflammatory and antiallergic pharmacological effects. This study aimed to investigate the inhibitory effect of fisetin on CU via MRGPRX2 and its possible molecular mechanisms. OVA/SP co-stimulated and SP-stimulated CU like murine models were used to evaluate the effect of fisetin on CU. MRGPRX2/HEK293 cells and LAD2 cells were used to perform the antagonism effect of fisetin on MC via MRGPRX2. The results indicated that fisetin prevented urticaria-like symptoms in murine CU models, and inhibited MCs activation by suppressing calcium mobilization and degranulation of cytokines and chemokines via binding to MRGPRX2. The bioinformatics analysis showed that fisetin might have an interaction relationship with Akt in CU. The western blotting experiments showed that fisetin downregulated the phosphorylation levels of Akt, P38, NF-κB, and PLCγ in C48/80 activated LAD2 cells. Fisetin alleviates CU progression by inhibiting mast cell activation via MRGPRX2, which may be a novel therapeutic candidate for CU.

Safety and efficacy of lirentelimab in patients withrefractory indolent systemic mastocytosis: a first-in-human clinical trial.

Indolent systemic mastocytosis (ISM) is characterized by excessive mast cell (MC) accumulation and MC-driven signs and symptoms. Currently used therapies are not approved and have limited efficacy. Lirentelimab (AK002) is a monoclonal antibody against sialic acid-binding immunoglobulin-like lectin (Siglec)-8 that inhibits MC activation. To determine the safety, tolerability and efficacy of lirentelimab in reducing the symptoms of ISM. At a specialty centre for mastocytosis in Germany, we conducted a phase I first-in-human single-ascending and multidose clinical trial of lirentelimab in patients with ISM. Eligible adults had World Health Organization-confirmed ISM and an unsatisfactory response to available treatment. In part A, patients received a single dose of lirentelimab 0.0003, 0.001, 0.003, 0.01 or 0.03 mg kg-1; in part B, patients received one lirentelimab dose of 0.3 mg kg-1 or 1.0 mg kg-1; and in part C, patients received either 1.0 mg kg-1 lirentelimab every 4 weeks for 6 months or ascending doses of lirentelimab (one dose of 1 mg kg-1 followed by five doses of 3-10 mg kg-1 every 4 weeks). The primary endpoint was safety/tolerability. Secondary endpoints included changes from baseline in Mastocytosis Symptom Questionnaire (MSQ), Mastocytosis Activity Score (MAS) and Mastocytosis Quality of Life Questionnaire (MC-QoL) scores at 2 weeks after the final dose. In 25 patients with ISM (13 in parts A + B and 12 in part C; median age 51 years, 76% female, median 4.6 years from diagnosis), the most common treatment-related adverse events (AEs) were feeling hot (76%) and experiencing a headache (48%). No serious AEs occurred. Median MSQ and MAS symptom severity scores in part C improved (vs. baseline) across all symptoms [MSQ: skin (38-56%), gastrointestinal (49-60%), neurological (47-59%), musculoskeletal (26-27%); MAS: skin (53-59%), gastrointestinal (72-85%), neurological (20-57%), musculoskeletal (25%)]. Median MC-QoL scores improved across all domains: symptoms (39%), social life/functioning (42%), emotions (57%) and skin (44%). Lirentelimab was generally well tolerated and improved symptoms and quality of life in patients with ISM. The therapeutic potential of lirentelimab should be considered for ISM.

Mast Cells in Upper and Lower Airway Diseases: Sentinels in the Front Line.

Mast cells (MCs) are fascinating cells of the innate immune system involved not only in allergic reaction but also in tissue homeostasis, response to infection, wound healing, protection against kidney injury, the effects of pollution and, in some circumstances, cancer. Indeed, exploring their role in respiratory allergic diseases would give us, perhaps, novel therapy targets. Based on this, there is currently a great demand for therapeutic regimens to enfeeble the damaging impact of MCs in these pathological conditions. Several strategies can accomplish this at different levels in response to MC activation, including targeting individual mediators released by MCs, blockade of receptors for MC-released compounds, inhibition of MC activation, limiting mast cell growth, or inducing mast cell apoptosis. The current work focuses on and summarizes the mast cells' role in pathogenesis and as a personalized treatment target in allergic rhinitis and asthma; even these supposed treatments are still at the preclinical stage.

Caffeic acid methyl ester inhibits mast cell activation through the suppresion of MAPKs and NF-κB signaling in RBL-2H3 cells

Anti-inflammatory effects of caffeic acid derivatives have been widely reported. However, the effect of caffeic acid methyl ester (CAME) on the anti-allergic effect in mast cells has not been elucidated. The present study was aimed to investigate the anti-allergic properties of CAME and its underlying mechanism. Rat basophilic leukemia (RBL-2H3) cells were incubated withphorbol-12-myristate-13-acetate (PMA) and a calcium ionophore, A23187 to induce mast cell activation. Anti-allergic effect of CAME was examined by measuring cytokine, histamine and β-hexosaminidase release. Western blotting was conducted to determine cyclooxygenase-2 (COX-2) expression, Mitogen-activated protein kinases (MAPKs) activation and nuclear factor-κB (NF-κB) translocation. CAME significantly suppressed PMA/A23187-induced TNF-α secretion, and β-hexosaminidase and histamine release in a concentration-dependent manner. Furthermore, CAME significantly attenuated PMA/A23187-induced COX-2 expression and nuclear translocation of NF-κB. CAME significantly suppressed PMA/A23187-induced increased phosphorylation of p38, ERK and JNK RBL-2H3 cells. The results demonstrate that CAME significantly attenuates anti-allergic action by suppressing degranulation of mast cells through the suppression of MAPKs/NF-κB signaling pathway in RBL-2H3 cells.

Siglec-9 is an inhibitory receptor on human mast cells in vitro

Mast cell activation is critical for the development of allergic diseases. Ligation of sialic acid-binding immunoglobin-like lectins (Siglecs), such as Siglec-6, -7, and -8 as well as CD33, have been shown to inhibit mast cell activation. Recent studies showed that human mast cells express Siglec-9, an inhibitory receptor also expressed by neutrophils, monocytes, macrophages, and dendritic cells. We aimed to characterize Siglec-9 expression and function in human mast cells invitro. We assessed the expression of Siglec-9 and Siglec-9 ligands on human mast cell lines and human primary mast cells by real-time quantitative PCR, flow cytometry, and confocal microscopy. We used a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing approach to disrupt the SIGLEC9 gene. We evaluated Siglec-9 inhibitory activity on mast cell function by using native Siglec-9 ligands, glycophorin A(GlycA), and high-molecular-weight hyaluronic acid, a monoclonal antibody against Siglec-9, and coengagement of Siglec-9 with the high-affinity receptor for IgE (FcεRI). Human mast cells express Siglec-9 and Siglec-9 ligands. SIGLEC9 gene disruption resulted in increased expression of activation markers at baseline and increased responsiveness to IgE-dependent and IgE-independent stimulation. Pretreatment with GlycA or high-molecular-weight hyaluronic acid followed by IgE-dependent or -independent stimulation had an inhibitory effect on mast cell degranulation. Coengagement of Siglec-9 with FcεRI in human mast cells resulted in reduced degranulation, arachidonic acid production, and chemokine release. Siglec-9 and its ligands play an important role in limiting human mast cell activation invitro.

1004 Dermal extracellular matrix inhibits mast cell activation to skin commensal bacteria

1004 Dermal extracellular matrix inhibits mast cell activation to skin commensal bacteria

Study on the mechanism of electroacupuncture repairing intestinal barrier via regulating mast cell in rats with diarrhea-predominant irritable bowel syndrome

To observe the effect of electroacupuncture (EA) on mast cell activation-related substances and intestinal barrier function in diarrhea-predominant irritable bowel syndrome (IBS-D) model rats, so as to explore its underlying mechanisms. Thirty female SD rats were randomly divided into control group, model group and EA group, with 10 rats in each group. IBS-D model was established by chronic unpredictable mild stress combined with senna solution gavage. Rats in the EA group received EA treatment (2 Hz/15 Hz，0.1-1.0 mA) at "Zusanli" (ST36), "Taichong"(LR3) and "Tianshu"(ST25), 20 min per day, for a total of 14 days, with sides alternated daily. Visceral pain threshold was used to evaluate visceral hypersensitivity, diarrhea index was used to evaluate diarrhea degree. After all treatments, the pathological scores of colon were recorded after HE staining, the contents of cholecystokinin (CCK), substance P (SP), tryptase (TPS) and adenosine triphosphate (ATP) in colon were detected by ELISA, and the expressions of colonic tight junction protein ZO-1 and occludin were detected by Western blot. Compared with the control group, the visceral pain threshold, the expression levels of colonic ZO-1 and occludin proteins decreased (P<0.01), while the diarrhea index, the contents of colonic CCK, SP, TPS and ATP were significantly increased (P<0.01) in the model group. After intervention, in comparison with the model group, the visceral pain thre-shold, the protein expression levels of colonic ZO-1 and occludin protein increased (P<0.01), while the diarrhea index, the contents of colonic CCK, SP, TPS and ATP were significantly decreased (P<0.01) in the EA group. EA can significantly alleviate the symptoms of visceral hypersensitivity and diarrhea in IBS-D rats. Its mechanism may be related to down-regulating colonic CCK, SP, TPS and ATP, inhibiting mast cell activation and degranulation, and up-regulating colonic barrier tight junction proteins.

DPP4 Inhibitor Sitagliptin Reduces Inflammatory Responses and Mast Cell Activation in Allergic Rhinitis

Introduction: DPP4 is thought to be involved in certain immune processes and plays an important role in allergic reactions in the lungs. The effect of the DPP4 inhibitor sitagliptin on the effector phase of allergic rhinitis (AR) in ovalbumin (OVA)-sensitized mice and on mast cell degranulation in vitro was assessed. Methods: The AR mouse model was established by intraperitoneal injection combined with OVA intranasal method. OVA was injected intraperitoneally 3 times for the first 2 weeks, and the mice were subsequently given DPP4 inhibitors by oral gavage, accompanied by an OVA intranasal challenge. The impacts of DPP4 inhibitors on DPP4 levels in mouse model were determined. Nasal mucosa tissue was collected for H&E staining and toluidine blue staining. Immunoglobulin E (IgE) levels and histamine levels were analyzed, and IL-4, IL-5, and IL-12 as well as IFN-γ levels were assessed. Following the treatment of dinitrophenol (DNP)-IgE or DNP-IgE plus sitagliptin in RBL-2H3 cells, β-hexosaminidase activity was analyzed and toluidine blue staining was performed. Results: DPP4 level was reduced in AR patients, as well as in AR mouse models. Nasal allergic symptoms such as sneezing and nose-scratching showed high frequency in OVA-induced mice. Sitagliptin treatment during the intranasal challenge of OVA decreased DPP4 levels, suppressed allergic symptoms, eosinophil infiltration, IgE levels, mast cell infiltration, as well as the levels of inflammatory cytokines. We further found that sitagliptin inhibited mast cell activation and histamine levels in vitro. Conclusion: Sitagliptin suppresses the effector phase of AR, and this mechanism is partly attributed to the suppression of inflammatory response and mast cell degranulation.

Myricetin alleviated immunologic contact urticaria and mast cell degranulation via the PI3K/Akt/NF-κB pathway.

Immunologic contact urticaria (ICU) is characterized by the wheal and flare reaction from direct contact with a chemical or protein agent, which involves a type I hypersensitivity mediated by allergen-specific immunoglobulin E (sIgE). Myricetin (Myr), a bioactive flavonoid, exhibits antiinflammatory activities. Our results showed that treatment with Myr could alleviate ICU symptoms, including a decrease in the number of wheals and scratching, and inhibit ear swelling in the IgE/DNFB-induced mice. The serum level of IgE, histamine, interleukin (IL)-4, TNF-α, and MCP-1 were reduced in Myr-treated mice. Myr also attenuated mast cells (MCs) degranulation and H-PGDS, TSLP, IL-33, PI3K, Akt, and NF-κB mRNA levels in ICU model. The IgE-mediated anaphylaxis mouse models demonstrated anti-allergic effects of Myr. In vitro analysis showed that Myr reduced IgE-induced calcium (Ca2+ ) influx, suppressed degranulation, and chemokine release in LAD2 cells (human primary mast cells). Myr can significantly inhibited PLCγ1, Akt, NF-κB, and p38 phosphorylation. In conclusion, the study demonstrated that Myr alleviate ICU symptoms and inhibit mast cell activation via PI3K/Akt/NF-κB signal pathway.

Cannabidiol Attenuates Chronic and Acute Hyperalgesia in Sickle Mice By Reducing Inflammation and Oxidative Stress

Pain is a major comorbidity of sickle cell disease (SCD) leading to hospitalization, opioid use and reduced survival. It can present as both chronic pain and/or unpredictable episodes of intense acute pain. Hydroxyurea (HU) is the mainstream FDA approved treatment for SCD, but its effect on reducing pain remains to be understood. A larger number of people with SCD use cannabis products for pain relief compared to those with other conditions. Cannabidiol (CBD) is one of the major constituents of Cannabis sativa, second to tetrahydrocannabinol, and has gained attention for its ability to treat pain without intoxicating side effects. CBD has been shown to decrease inflammation, oxidative stress, and inhibit mast cell activation, all of which occur in SCD. Thus, we hypothesize that CBD will ameliorate both chronic and acute hyperalgesia in humanized homozygous BERK sickle mice (called sickle) by inhibiting mast cell activation and decreasing inflammation and oxidative stress. To simulate the clinical condition, we treated female sickle mice intraperitoneally with [i] vehicle (1:1:18 DMSO:Tween-20:saline), [ii] HU (50 mg/kg/d HU), [iii] CBD (20 mg/kg/d) or [iv] HU + CBD and determined their effect on chronic and acute hyperalgesia (pain). Sickle mice treated with synthetic CBD alone or cotreatment with HU+CBD daily showed significantly reduced chronic mechanical (p<0.001) and cold (p<0.001) hyperalgesia compared to baseline after 7 days of treatment, which was maintained for up to 14 days. HU decreased mechanical (p<0.01) but not cold hyperalgesia after 14 days compared to baseline. Thus, CBD independently attenuates chronic hyperalgesia, whereas HU may have a modest effect on chronic pain. Following the initial 14 days of treatment above, we incited acute hyperalgesia by treating sickle mice with hypoxia/reoxygenation (H/R; 3 hours of hypoxia at 8% O2 and 92% N2, followed by 1 hour of reoxygenation at normoxia) on days 15 (H/R-1) and 18 (H/R-2). We observed that CBD, HU, and HU+CBD treatments were able to prevent an increase in H/R-incited hyperalgesia (acute response). CBD alone and HU+CBD significantly reduced mechanical (p<0.001) and cold hyperalgesia (p<0.001) compared to baseline following incitement of both H/R-1 and H/R-2, and up to 25 days, the last period of observation. HU alone did not show a significant decrease in mechanical or cold hyperalgesia compared to baseline following incitement of either H/R event, except for cold hyperalgesia 72h post-H/R-2 (p<0.05). CBD and HU+CBD treatments also reduced non-evoked cold avoidance compared to baseline in sickle mice, which spent significantly more time (p<0.01) in a cold chamber (4°C) 7d after H/R-2 (day 25), but HU alone did not. Thus, HU has a modest or no effect on different features of sickle pain, while CBD is able to ameliorate both chronic and acute pain. We next investigated the mechanism of CBD's analgesic effect in sickle mice. Following 9 days of daily treatment, we observed that CBD decreased total and degranulating mast cells (p<0.05 and p<0.01, respectively) in the skin compared to vehicle, and a reduction in tryptase (p<0.05), a marker of mast cell activation, in the skin secretagogue. CBD treatment decreased substance P (p=0.05) and malondialdehyde, (p<0.05), markers of neuroinflammation and oxidative stress respectively, in the skin secretagogue, and serum amyloid P (p<0.05), a marker of inflammation, in plasma. CBD significantly decreased inflammatory cytokines IL-3, which promotes mast cell proliferation, TNFα, a hallmark feature of cytokine storm, and MIP-1α and RANTES, which contribute to leukocyte recruitment. Thus, CBD attenuates inflammation, neuroinflammation and oxidative stress in sickle mice and may ameliorate leukocyte activities, a hallmark feature of SCD. We demonstrate that CBD is effective in attenuating chronic hyperalgesia and preventing acute pain by decreasing inflammation and oxidative stress. The effect of HU on reducing pain following H/R and chronic pain are modest and specific to certain characteristic features of sickle pain. Importantly, HU does not appear to interfere with the analgesic effect of CBD in sickle mice, which shows promise for CBD treatment in persons with SCD on HU. The availability of a >99% CBD-extract (Epidiolex) approved by the FDA to treat some forms of epilepsy may help facilitate clinical trials for assessing the effects of CBD on pain in persons with SCD.

New furofuran and tetrahydrofuran lignans from the flower buds of Magnolia biondii Pamp and their antiallergic effects

The dried flower buds of Magnolia biondii Pamp (herbal name, Xin-Yi) are a traditional Chinese medicine with a long history of clinical use in the treatment of allergic rhinitis and sinusitis. However, the constituents responsible for its antiallergic effects remain clearly unidentified. In the present study, totally 33 lignans were obtained from M. biondii. Among them, two novel furofuran lignans (1 and 2), two novel tetrahydrofuran lignans (3 and 4), and other 16 known lignans were isolated first time from M. biondii. The antiallergic effects of compounds 1-33 on mouse bone marrow-derived mast cells (BMMCs) degrunaliton were evaluated and results showed that compounds 7, 8, 13, 15 and 18 could significantly inhibited β-hex release on BMMCs. The results proved that furofuran and tetrahydrofuran lignans were the main constituents in M. biondii and their antiallergic effects were related with suppressing mast cell activation.

An Amide Alkaloid Isolated from Ephedra sinica Ameliorates OVA-Induced Allergic Asthma by Inhibiting Mast Cell Activation and Dendritic Cell Maturation.

Asthma, which is a chronic inflammatory disease of the airways, is usually caused by allergens in which various structures and immune cells are involved. Ephedra sinica, the most commonly used Chinese medicine, has significant clinical effects on asthma, but its components are complex and the mechanism of action has not been fully elucidated. Among its components, we identified an amide alkaloid (EB-A) and investigated its anti-asthmatic activity and the underlying mechanisms. In this study, we replicated an OVA-sensitized/challenged allergic asthma mouse model, and divided the mice into a model (OVA) group, positive drug (Y, 0.5 mg/kg/day) group, and EB-A treatment with low (Low, 10 mg/kg/day) and high dose (High, 20 mg/kg/day) groups. Asthma-related features were analyzed through the airway hyperresponsiveness (AHR), cough and wheeze indexes, allergen-specific IgE, prostaglandin D2 (PDG2), and lung histology in mice. The levels of apoptosis and reactive oxygen species (ROS) in the primary lung cells, cytokines in the serum and broncho-alveolar lavage fluid (BALF), and proteinase-activated receptor-2 (PAR2) pathway activation in the lung tissue were measured to evaluate the inflammatory injury and lung epithelial barrier damage in the mice. Dendritic cell (DC) maturation and mast cell (MC) activation were verified in vitro and in vivo. Furthermore, the effect of a PAR2 activation in lung epithelial cells on the maturation of DCs was evaluated by the co-culture system of (human bronchial epithelial cell lines) 16HBE and bone marrow-derived dendritic cells (BMDCs). The results showed that EB-A inhibited the typical asthmatic phenotypes, as well as lung injury and inflammation, MC activation and degranulation, and DC maturation in the OVA-sensitized/challenged BALB/c mice. In addition, EB-A inhibited the expression of PAR2 in the lung epithelial cells and significantly interfered with the maturation of DCs after inhibiting PAR2. Taken together, our study firstly demonstrated that EB-A could ameliorate OVA-induced allergic asthma by inhibiting MC activation and DC maturation, and the molecular mechanism of EB-A's anti-asthmatic activity might be mediated by inhibiting PAR2. Our data provide a molecular justification for the use of EB-A in the treatment of allergic asthma.

Pretreatment with propofol restores intestinal epithelial cells integrity disrupted by mast cell degranulation in vitro

Propofol has been shown to against intestinal reperfusion injury when treated either before or after ischemia, during which mast cell could be activated. The aim of this study was to evaluate the role of propofol in restoring the intestinal epithelial cells integrity disrupted by mast cell activation or the released tryptase after activation in vitro. We investigated the effect of: (1) tryptase on Caco-2 monolayers in the presence of PAR-2 inhibitor or propofol, (2) mast cell degranulation in a Caco-2/LAD-2 co-culture model in the presence of propofol, and (3) propofol on mast cell degranulation. Epithelial integrity was detected using transepithelial resistance (TER) and permeability to fluorescein isothiocyanate (FITC)-dextran (the apparent permeability coefficient, Papp). The expression of junctional proteins zonula occludens-1 (ZO-1/TJP1) and occludin were determined using western blot analysis and immunofluorescence microscopy. The intracellular levels of reactive oxidative species (ROS) and Ca2+ were measured using flow cytometry. Tryptase directly enhanced intestinal barrier permeability as demonstrated by significant reductions in TER, ZO-1, and occludin protein expression and concomitant increases in Papp. The intestinal barrier integrity was restored by PAR-2 inhibitor but not by propofol. Meanwhile, mast cell degranulation resulted in epithelial integrity disruption in the Caco-2/LAD-2 co-culture model, which was dramatically attenuated by propofol. Mast cell degranulation caused significant increases in intracellular ROS and Ca(2+) levels, which were blocked by propofol and NAC. Propofol pretreatment can inhibit mast cell activation via ROS/Ca(2+) and restore the intestinal barrier integrity induced by mast cell activation, instead of by tryptase.

Mast Cells and Vitamin D Status: A Clinical and Biological Link in the Onset of Allergy and Bone Diseases.

The immune system is made up by an extremely composite group of cells, whose regulated and harmonious activity is fundamental to maintain health. The mast cells are an essential effector of inflammatory response which is characterized by a massive release of mediators accumulated in cytoplasmic secretory granules. However, beyond the effects on immune response, mast cells can modify bone metabolism and are capable of intervening in the genesis of pathologies such as osteoporosis and osteopenia. Vitamin D is recognized to induce changes in bone metabolism, but it is also able to influence immune response, suppressing mast cell activation and IgE synthesis from B cells and increasing the number of dendritic cells and IL-10-generating regulatory T cells. Vitamin D deficit has been reported to worsen sensitization and allergic manifestations in several different experimental models. However, in clinical situations, contradictory findings have been described concerning the correlation between allergy and vitamin D deficit. The aim of this review was to analyze the close relationships between mast cells and vitamin D, which contribute, through the activation of different molecular or cellular activation pathways, to the determination of bone pathologies and the onset of allergic diseases.

α-Asarone alleviates allergic asthma by stabilizing mast cells through inhibition of ERK/JAK2-STAT3 pathway.

Asthma is a heterogeneous disease related to numerous inflammatory cells, among which mast cells play an important role in the early stages of asthma. Therefore, treatment of asthma targeting mast cells is of great research value. α-Asarone is an important anti-inflammatory component of the traditional Chinese medicine Acorus calamus L, which has a variety of medicinal values. To investigate whether α-asarone can alleviate asthma symptoms and its mechanism. In this study, we investigated the effect of α-asarone on mast cell activation in vivo and in vitro. The release of chemokines or cytokines, AHR (airway hyperresponsiveness), and mast cell activation were examined in a mast cell-dependent asthma model. Western blot was performed to determine the underlying pathway. α-Asarone inhibited the degranulation of LAD2 (laboratory allergic disease 2) cells and decreased IL-8, MCP-1, histamine, and TNF-α in vitro. α-Asarone reduced paw swelling and leakage of Evans blue, as well as serum histamine, CCL2, and TNF-α in vivo. In the asthma model, α-asarone showed an inhibitory effect on AHR, inflammation, mast cells activation, infiltration of inflammatory cells, and the release of IL-5 and IL-13 in lung tissue. α-Asarone decreased the levels of phosphorylated JAK2, phosphorylated ERK, and phosphorylated STAT3 induced by C48/80. Our findings suggest that α-asarone alleviates allergic asthma by inhibiting mast cell activation through the ERK/JAK2-STAT3 pathway.

597 Development of LY3454738, an agonistic antibody to human CD200R

CD200R is an immune receptor of the IgG family that is primarily expressed on cells of the myeloid lineage and was recently identified as a marker for Th2 biology (Blom et al 2017). In vivo studies with knockout mice of either the receptor or its ligand, CD200, have demonstrated that it is an inhibitory receptor capable of negatively regulating immune responses. Previous work using agonistic antibodies to mouse CD200R showed inhibition of mast cell activation in vitro and in vivo (Cherwinski et al 2005) as well as efficacy in multiple preclinical models of autoimmune diseases.

LB975 The role of gut flora metabolite butyrate in inhibiting mast cell activation via deacetylase in chronic spontaneous urticaria

Chronic spontaneous urticaria (CSU) is an immune-related skin disease characterized by abnormal activation of mast cells (MCs). With the advanced research on the gut flora in immune-related diseases, it is suggested that dysbiosis of the gut flora may contribute to the pathogenesis of CSU, but the mechanisms involved are unknown. Butyrate, a metabolite of the gut flora, is involved in a variety of cellular physiological processes as a histone deacetylase inhibitor (HDACi) and exerts beneficial effects on the intestinal tract and other organs.

Ligation of Siglec-9 inhibits FcɛRI-dependent mediator release from human mast cells

Abstract Mast cell activation is critical for the development of allergic diseases. Ligation of Sialic acid-binding immunoglobin-like lectins (Siglecs) such as Siglec-7 and 8 has been shown to inhibit mast cell activation and is considered one of the main approaches to reduce mast cell contribution to allergic disease. Recent high throughput studies provided evidence that human mast cells express Siglec-9, an inhibitory receptor that is mainly expressed by innate immune cells such as neutrophils, monocytes and eosinophils. Based on this evidence, we aimed to examine Siglec-9 expression and function in human mast cells. Flow cytometry analysis showed that Siglec-9 is expressed in the human mast cell lines LAD2, LUVA, and HMC-1, and in peripheral blood-derived cultured human mast cells (PBCMCs). The expression of Siglec-9 in PBCMCs peaks at week 5 of culture and correlates positively with the expression of the high affinity receptor for IgE (FcɛRI). Pre-treatment of human mast cells with the Siglec-9 agonists glycophorin A or high molecular weight hyaluronic acid (HMW-HA) followed by FcɛRI-dependent stimulation has an inhibitory effect on mast cell degranulation. SIGLEC9 gene disruption by CRISPR/Cas9 editing resulted in a significant reduction in Siglec-9 expression in LAD2 cells that also became impervious to inhibition by Siglec-9 agonists. Together, our data shows that human mast cells express Siglec-9 and that engaging this inhibitory receptor can reduce mast cell degranulation.