Allergic Inflammatory Response Research Articles

Extracellular vesicles of Echinococcus granulosus have therapeutic effects in allergic airway inflammation.

Previous studies have shown that Echinococcus granulosus cystic fluid can alleviate Th2 allergic airway inflammatory responses by increasing the number of CD4+ CD25+ Foxp3+ T (regulatory T; Treg) cells. Parasite-derived extracellular vesicles (EV) are known to not only promote parasite infection by communicating between parasites but also regulate the inflammatory response by acting as an immunomodulatory agent in the host. To evaluate the effect of EV extracted from the cystic fluid of E. granulosus on allergic airway inflammation, gene expression was investigated after administering EV to mouse lung epithelial cells (MLE-12) following 2h of pretreatment with Aspergillus proteins. An allergic airway inflammation animal model was used to investigate the regulation of the inflammatory response by EV and induced with ovalbumin. EV treatment significantly reduced airway resistance and the number of eosinophils and other immune cells in the bronchoalveolar lavage fluid and Th2- and Th17-related cytokine levels. EV pretreatment decreased the number of IL-4+ CD4+ T cells and increased the number of Treg cells in the lung-draining lymph nodes and spleen. Echinococcus granulosus cystic fluid derived EV ameliorated Th2 allergic airway inflammatory through Treg cells, similar to whole cystic fluid treatment. Thus, EV may be important immunomodulatory molecules in cystic fluid.

눈연꽃 추출물의 Lyn과 Syk 인산화 억제를 통한 알레르기성 염증 억제 효과

Background: Snow lotus [Saussurea involucrata (Kar. & Kir.) Sch. Bip.] is used in Chinese herbal medicine because of its antioxidant and anti-inflammatory effects. The mechanism of its anti-inflammatory effect on allergic response is unknown.<BR>Methods and Results: We evaluated the effect of the aqueous extract of S. involucrata flowers on the allergic inflammatory response in dinitrophenyl-immunoglobulin E (DNP-IgE)-activated RBL-2H3 cells. Cell viability and β-hexosaminidase release from the activated RBL-2H3 cells were evaluated. The levels of proinflammatory molecules including tumor necrosis factor-alpha (TNF-α), interleukin (IL)-4, IL-10, IL-1β, and prostaglandin E2 in RBL-2H3 cells treated with 5% and 10% S. involucrata extract. Treatment with S. involucrata extract significantly suppressed the phosphorylation of protein kinase B (AKT), p38, c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK)1/2, and mitogen-activiated protein kinase (MEK) in a dose-dependent manner. S. involucrata extract also inhibited the Fc epsilon receptor 1 signaling pathway involving phosphorylation of Lyn, Syk, and phosphoinositide 3-kinase (PI3K), which is associated with the PI3K-AKT-ERK pathway and cytokine expression. A major mechanism of action of S. involucrata extract was to reduce the extent of the DNP-IgE-induced cytoskeletal change from globular to filamentous actin in RBL-2H3 cells.<BR>Conclusions: S. involucrata extract mediates its antiallergic effect by suppressing inflammation. The findings will be valuable in the development of S. involucrata extract as a phytomedicine with minimal side effects for allergic diseases.

Virtual discovery of a hetero-cyclic compound from the Universal Natural Product Database (UNPD36) as a potential inhibitor of interleukin-33: molecular docking and dynamic simulations

Interleukin (IL)-33 is a cytokine implicated in several inflammatory and autoimmune diseases. Upon binding to its receptor ST2, IL-33 activates allergic inflammatory responses. To block this protein-protein interaction with a potential anti-allergic agent, we screened Universal Natural Product Database (UNPD) using a combined approach of molecular docking and dynamic simulations. Six hundred compounds with high gastrointestinal absorption properties from the UNPD were retrieved and subjected to molecular docking using Autodock Vina, out of which four hetero-cyclic compounds (UNPD36, UNPD2045, UNPD8905, UNPD122514) were found to have binding energy score of < −7.0 Kcal/mol. Further analysis from 100 ns MD simulation of the best hit (UNPD36) revealed that IL-33_UNPD36 complex reached average stability at RMSD of 2.7 Å, and residues involved in the interaction showed lower fluctuations compared to the residues at the β4–β5 and β11–β12 loop region. Further molecular docking using Autodock 4.2 was carried out to determine the binding orientation of UNPD36. Using GROMACS, additional 50 ns MD simulations and MM-PBSA calculation were performed on this complex. Finally, chemoinformatic studies revealed that the UNPD36 had drug-like and pharmacokinetic profiles as well as potentials for oral and topical applications, in addition to good safety profile. Thus, it was concluded that a hetero-cyclic compound with chromone moiety (UNPD36) had a good and stable binding mode to serve as potential inhibitor of IL-33 and/or may provide a scaffold for further optimization toward the design of more potent inhibitors for application in the treatment of respiratory allergies. Communicated by Ramaswamy H. Sarma

New Biomarkers of Hymenoptera Venom Allergy in a Group of Inflammation Factors

Hymenoptera venom allergy significantly affects the quality of life. Due to the divergences in the results of the available test and clinical symptoms of patients, the current widely applied diagnostic methods are often insufficient to classify patients for venom immunotherapy (VIT). Therefore it is still needed to search for new, more precise, and accurate diagnostic methods. Hence, this research aimed to discover new biomarkers of Hymenoptera venom allergy in a group of inflammation factors using set of multi-marker Bioplex panel. The adoption of a novel methodology based on Luminex/xMAP enabled simultaneous determination of serum levels of 37 different inflammatory proteins in one experiment. The study involved 21 patients allergic to wasp and/or honey bee venom and 42 healthy participants. According to univariate and multivariate statistics, soluble CD30/tumor necrosis factor receptor superfamily, member 8 (sCD30/TNFRSF8), and the soluble tumor necrosis factor receptor 1 (sTNF-R1) may be considered as effective prognostic factors, their circulating levels were significantly decreased in the allergy group (p-value < 0.05; the Area Under the Curve (AUC) ~0.7; Variable Importance in Projection (VIP) scores >1.2). The obtained results shed new light on the allergic inflammatory response and may contribute to modification and improvement of the diagnostic and monitoring methods. Further, large-scale studies are still needed to explain mechanisms of action of studied compounds and to definitively prove their usefulness in clinical practice.

Prostaglandin I2 signaling licenses Treg suppressive function and prevents pathogenic reprogramming.

Tregs restrain both the innate and adaptive immune systems to maintain homeostasis. Allergic airway inflammation, characterized by a Th2 response that results from a breakdown of tolerance to innocuous environmental antigens, is negatively regulated by Tregs. We previously reported that prostaglandin I2 (PGI2) promoted immune tolerance in models of allergic inflammation; however, the effect of PGI2 on Treg function was not investigated. Tregs from mice deficient in the PGI2 receptor IP (IP KO) had impaired suppressive capabilities during allergic airway inflammatory responses compared with mice in which PGI2 signaling was intact. IP KO Tregs had significantly enhanced expression of immunoglobulin-like transcript 3 (ILT3) compared with WT Tregs, which may contribute to the impairment of the IP KO Treg's ability to suppress Th2 responses. Using fate-mapping mice, we reported that PGI2 signaling prevents Treg reprogramming toward a pathogenic phenotype. PGI2 analogs promoted the differentiation of naive T cells to Tregs in both mice and humans via repression of β-catenin signaling. Finally, a missense variant in IP in humans was strongly associated with chronic obstructive asthma. Together, these data support that PGI2 signaling licenses Treg suppressive function and that PGI2 is a therapeutic target for enhancing Treg function.

Linggan Wuwei Jiangxin formula ameliorates airway hyperresponsiveness through suppression of IL-1β and IL-17A expression in allergic asthmatic mice especially with diet-induced obesity.

BackgroundObese asthma represents a disease phenotype, which is associated with worse disease control and unresponsiveness to standard anti-inflammatory regimens, including inhaled corticosteroids. Obesity-related innate airway hyperresponsiveness (AHR) plays a role in this asthma phenotype via activation of the IL-1β/innate lymphoid cell 3 (ILC3)/IL-17A pathway. Linggan Wuwei Jiangxin (LGWWJX) formula may be a promising therapeutic option for obese asthma according to traditional Chinese medicine theory, clinical experience and related research.MethodsThe murine model of allergic asthma with obesity was induced by ovalbumin (OVA) sensitization and challenge in combination with a high fat diet (HFD). LGWWJX formula intervention was oral administrated. AHR and bronchoalveolar lavage fluid (BALF) cellularity were measured. Lung and liver histopathology assessment was performed by haematoxylin and eosin (H&E) staining. IL-1β and IL-17A in BALF and serum were evaluated by ELISA. Additionally, the influence of different concentrations of LGWWJX formula on IL-1β stimulated IL-17A mRNA expression in ILC3 cells was evaluated in vitro.ResultsLGWWJX treatment significantly reduced AHR and allergic airway inflammatory responses in asthmatic mice, as measured by pulmonary histopathology and BALF cellularity, and these effects were more pronounced in obese asthmatic mice. While eosinophil infiltration in BALF was suppressed with LGWWJX treatment in non-obese asthmatic mice, neutrophils and basophils were significantly decreased in obese asthmatic mice. Notably, LGWWJX also demonstrated remarkable efficacy for weight loss and improvements in hepatic steatosis in mice fed with a HFD. Furthermore, the protein levels of IL-1β in both serum and BALF, as well as those of BALF IL-17A, declined with LGWWJX intervention in both obese and non-obese asthmatic mice, and results from ex-vivo experiments found that LGWWJX significantly attenuated the expression of IL-17A in ILC3 cells with or without stimulation by IL-1β.ConclusionsLGWWJX may exert a protective effect on asthmatic individuals, especially those with concurrent obesity, most likely through mechanisms including the inhibition of the IL-1β/ILC3/IL-17A/AHR axis, anti-inflammatory effects, weight loss, and the regulation of lipid metabolism. This suggests a promising role of LGWWJX, alone or in combination with anti-inflammatory agents, for the treatment of obese asthma.

The magnitude of airway remodeling is not altered by distinct allergic inflammatory responses in BALB/c versus C57BL/6 mice but matrix composition differs.

Allergic airway inflammation is heterogeneous with variability in immune phenotypes observed across asthmatic patients. Inflammation has been thought to directly contribute to airway remodeling in asthma, but clinical data suggest that neutralizing type 2 cytokines does not necessarily alter disease pathogenesis. Here, we utilized C57BL/6 and BALB/c mice to investigate the development of allergic airway inflammation and remodeling. Exposure to an allergen cocktail for up to 8weeks led to type 2 and type 17 inflammation, characterized by airway eosinophilia and neutrophilia and increased expression of chitinase-like proteins in both C57BL/6 and BALB/c mice. However, BALB/c mice developed much greater inflammatory responses than C57BL/6 mice, effects possibly explained by a failure to induce pathways that regulate and maintain T-cell activation in C57BL/6 mice, as shown by whole lung RNA transcript analysis. Allergen administration resulted in a similar degree of airway remodeling between mouse strains but with differences in collagen subtype composition. Increased collagen III was observed around the airways of C57BL/6 but not BALB/c mice while allergen-induced loss of basement membrane collagen IV was only observed in BALB/c mice. This study highlights a model of type 2/type 17 airway inflammation in mice whereby development of airway remodeling can occur in both BALB/c and C57BL/6 mice despite differences in immune response dynamics between strains. Importantly, compositional changes in the extracellular matrix between genetic strains of mice may help us better understand the relationships between lung function, remodeling and airway inflammation.

Bacteroides thetaiotaomicron Ameliorates Experimental Allergic Airway Inflammation via Activation of ICOS+Tregs and Inhibition of Th2 Response.

Inhibition of allergic airway diseases (AAD) by immunomodulation of the adaptive immune system through restoration of the enteric dysbiosis is an emerging therapeutic strategy. Patients with allergic rhinitis (n = 6) and healthy controls (n = 6) were enrolled, and gut microbiome composition analysis was performed by 16S rDNA sequencing. We also established an ovalbumin (OVA)-induced allergic airway inflammation murine model. Dysbiosis of the gut flora was observed in both AAD patients and the mice, with the decrease of the biodiversity and the quantity of the Bacteroidetes phylum. Oral application of Bacteroides (B.) thetaiotaomicron ameliorated the symptoms of OVA-induced airway hyperresponsiveness (AHR) and attenuated the airway inflammation in mice. In addition, nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF) from AAD mice orally administered with B. thetaiotaomicron showed reduced numbers of immune cells, and diminished secretion of T helper (Th)-2 cytokines (IL-4, IL-5, and IL-13) compared with the corresponding control mice, whereas the levels of Th1 cytokineIFN-γ was not changed in both the groups. When B. thetaiotaomicron was co-administered with metronidazole in AAD mice, the immunomodulatory effect was weakened and the allergic inflammatory response was aggravated. The ratios of CD4+Foxp3+ cells, CD4+ICOS+ T cells, CD4+ICOS+ Foxp3+ regulatory T cells, and IL-10-expressing CD4+Foxp3+ cells were increased in lymphocytes of spleen, mesenteric, and cervical lymph nodes of AAD mice administrated with B. thetaiotaomicron. Therefore, our data indicate that oral administration of B. thetaiotaomicron effectively inhibited the development of AAD in murine model; inhibition was mediated by the activation of Tregs and inhibition of Th2 response without promoting a Th1 response.

FcεR1-expressing nociceptors trigger allergic airway inflammation

Lung nociceptor neurons amplify immune cell activity and mucus metaplasia in response to an inhaled allergen challenge in sensitized mice. We sought to identify the cellular mechanisms by which these sensory neurons are activated subsequent to allergen exposure. We used calcium microscopy and electrophysiologic recording to assess whether vagal neurons directly respond to the model allergen ovalbumin (OVA). Next, we generated the first nociceptor-specific FcεR1γ knockdown (TRPV1Cre::FcεR1γfl/fl) mice to assess whether this targeted invalidation would affect the severity of allergic inflammation in response to allergen challenges. Lung-innervating jugular nodose complex ganglion neurons express the high-affinity IgE receptor FcεR1, the levels of which increase in OVA-sensitized mice. FcεR1γ-expressing vagal nociceptor neurons respond directly to OVA complexed with IgE with depolarization, action potential firing, calcium influx, and neuropeptide release. Activation of vagal neurons by IgE-allergen immune complexes, through the release of substance P from their peripheral terminals, directly amplifies TH2 cell influx and polarization in the airways. Allergic airway inflammation is decreased in TRPV1Cre::FcεR1γfl/fl mice and in FcεR1α-/- mice into which bone marrow has been transplanted. Finally, increased invivo circulating levels of IgE following allergen sensitization enhances the responsiveness of FcεR1 to immune complexes in both mouse jugular nodose complex ganglion neurons and human induced pluripotent stem cell-derived nociceptors. Allergen sensitization triggers a feedforward inflammatory loop between IgE-producing plasma cells, FcεR1-expressing vagal sensory neurons, and TH2 cells, which helps to both initiate and amplify allergic airway inflammation. These data highlight a novel target for reducing allergy, namely, FcεR1γ expressed by nociceptors.

Bivalent antibody pliers inhibit \u03b2-tryptase by an allosteric mechanism dependent on the IgG hinge

Human β-tryptase, a tetrameric trypsin-like serine protease, is an important mediator of allergic inflammatory responses in asthma. Antibodies generally inhibit proteases by blocking substrate access by binding to active sites or exosites or by allosteric modulation. The bivalency of IgG antibodies can increase potency via avidity, but has never been described as essential for activity. Here we report an inhibitory anti-tryptase IgG antibody with a bivalency-driven mechanism of action. Using biochemical and structural data, we determine that four Fabs simultaneously occupy four exosites on the β-tryptase tetramer, inducing allosteric changes at the small interface. In the presence of heparin, the monovalent Fab shows essentially no inhibition, whereas the bivalent IgG fully inhibits β-tryptase activity in a hinge-dependent manner. Our results suggest a model where the bivalent IgG acts akin to molecular pliers, pulling the tetramer apart into inactive β-tryptase monomers, and may provide an alternative strategy for antibody engineering.

DM-induced Hypermethylation of IR and IGF1R attenuates mast cell activation and airway responsiveness in rats.

Diabetes has been reported to modulate the airway smooth muscle reactivity and lead to attenuation of allergic inflammatory response in the lungs. In this study, we aimed to study the effect of insulin on cell activation and airway responsiveness in patients with diabetes mellitus (DM). The airway contraction in rat model groups including a non‐DM group, a non‐DM+INDUCTION group, a DM+INDUCTION group and a DM+INDUCTION+INSULIN group was measured to observe the effect of insulin on airway responsiveness. Radioenzymatic assay was conducted to measure the levels of histamine, and ELISA assay was conducted to measure bronchial levels of interleukin (IL)‐1b, tumour necrosis factor (TNF)‐a, cytokine‐induced neutrophil chemoattractant (CINC)‐1, P‐selectin and β‐hexosaminidase. The tension in the main and intrapulmonary bronchi of DM+INDUCTION rats was lower than that of the non‐DM+INDUCTION rats, whereas the treatment of insulin partly restored the normal airway responsiveness to OA in DM rats. The release of histamine was remarkably suppressed in DM+INDUCTION rats but was recovered by the insulin treatment. Also, OA significantly increased the levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in non‐DM rats, whereas insulin treatment in DM+INDUCTION rats partly restored the normal levels of IL‐1b, TNF‐a, CINC‐1 and P‐selectin in DM rats. Moreover, the expression of IR and IGF1R was evidently suppressed in DM rats, with the methylation of both IR and IGF1R promoters was aggravated in DM rats. Therefore, we demonstrated that DM‐induced hypermethylation inhibited mast cell activation and airway responsiveness, which could be reversed by insulin treatment.

Cornus officinalis Ethanolic Extract with Potential Anti-Allergic, Anti-Inflammatory, and Antioxidant Activities.

Atopic dermatitis (AD) is an allergic and chronic inflammatory skin disease. The present study investigates the anti-allergic, antioxidant, and anti-inflammatory activities of the ethanolic extract of Cornus officinalis (COFE) for possible applications in the treatment of AD. COFE inhibits the release of β-hexosaminidase from RBL-2H3 cells sensitized with the dinitrophenyl-immunoglobulin E (IgE-DNP) antibody after stimulation with dinitrophenyl-human serum albumin (DNP-HSA) in a concentration-dependent manner (IC50 = 0.178 mg/mL). Antioxidant activity determined using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity, ferric reducing antioxidant power assay, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) scavenging activity, result in EC50 values of 1.82, 10.76, and 0.6 mg/mL, respectively. Moreover, the extract significantly inhibits lipopolysaccharide (LPS)-induced nitric oxide (NO) production and the mRNA expression of iNOS and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) through attenuation of NF-κB activation in RAW 264.7 cells. COFE significantly inhibits TNF-α-induced apoptosis in HaCaT cells without cytotoxic effects (p < 0.05). Furthermore, 2-furancarboxaldehyde and loganin are identified by gas chromatography/mass spectrometry (GC-MS) and liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, respectively, as the major compounds. Molecular docking analysis shows that loganin, cornuside, and naringenin 7-O-β-D-glucoside could potentially disrupt the binding of IgE to human high-affinity IgE receptors (FceRI). Our results suggest that COFE might possess potential inhibitory effects on allergic responses, oxidative stress, and inflammatory responses.

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.

Oleanolic acid protects against mast cell-mediated allergic responses by suppressing Akt/NF-κB and STAT1 activation

BackgroundOleanolic acid (OA) is an active compound found in a variety of medicinal herbs and plants. Though OA has been widely attributed with a variety of biological activities, studies focused on its anti-allergic inflammation properties are insufficient. PurposeGiven the rapid increase in allergic diseases and the lack of fundamental treatment options, this study aimed to find a safe and effective therapy for allergic disorders. MethodsWe evaluated the inhibitory effect of OA on allergic inflammatory response and the possible mechanisms underlying the effect using phorbol-12-myristate 13-acetate plus calcium ionophore A23187 (PMACI)-stimulated human mast cell (HMC)-1, and a mouse model of compound 48/80-induced anaphylactic shock. ResultsOA suppressed pro-inflammatory cytokine expressions in PMACI-induced HMC-1 cells by inhibiting activation of the Akt, p38 mitogen-activated protein kinase (MAPK), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription (STAT) 1 signaling pathways. Moreover, OA showed a protective effect against compound 48/80-induced anaphylactic shock through inhibition of histamine release and immunoglobulin E level via regulation of NF-κB and STAT1 activation. ConclusionThe results showed that OA suppressed mast cell-mediated allergic response by transcriptional regulation. We suggest that OA has potential effect against allergic inflammatory disorders, including anaphylaxis, and might be a useful therapeutic agent for allergic disease.

Development of a specific immunoassay to selectively measure active tryptase in airway samples.

Aim: Tryptase is a tetrameric trypsin-like serine protease contained within the secretory granules of mast cells and is an important mediator of allergic inflammatory responses in respiratory diseases. Detection of active tryptase in the airway may provide important information about asthma and other respiratory diseases. Materials & Methods: An activity based probe has been incorported within an immunoassay to allow for measurement of active tryptase in human tissues. Results: A specific Simoa immunoassay to measure active tryptase in nasosorption samples was developed and qualified using an activity-based probe label and a specific antitryptase capture antibody. Conclusion: The assay was capable of measuring active tryptase in human samples, which will enable evaluation of the role of tryptase proteolytic activity in human disease.

Extract of Boehmeria nivea Suppresses Mast Cell-Mediated Allergic Inflammation by Inhibiting Mitogen-Activated Protein Kinase and Nuclear Factor-κB.

Mast cells are effector cells that initiate allergic inflammatory immune responses by inducing inflammatory mediators. Boehmeria nivea (Linn.) Gaudich is a natural herb in the nettle family Urticaceae that possesses numerous pharmacological properties. Despite the various pharmacological benefits of Boehmeria nivea, its effects on allergic inflammation have not yet been determined. Here, we investigated the effect of the ethanol extract of Boehmeria nivea (BNE) on degranulation rat basophilic leukemia (RBL)-2H3 mast cells stimulated with anti-dinitrophenyl (anti-DNP) and bovine serum albumin (BSA) during immunoglobulin E (IgE)-mediated allergic immune response. The results showed inhibition of the release of β-hexosaminidase and histamine from the cells. BNE suppressed pro-inflammatory cytokines (Tumor necrosis factor (TNF)-α, Interleukin (IL)-1β, and IL-6) and reduced T helper (Th)2 cytokine IL-4 expression and/or secretion correlated with the downregulation of p38, extracellular signal-regulated kinases (ERK) mitogen-activated protein kinase (MAPK), and nuclear factor-κB (NF-κB) signaling pathways in treated RBL-2H3 mast cells. In passive cutaneous anaphylaxis, treatment with BNE during IgE-mediated local allergic reaction triggered a reduction in mouse ear pigmentation and thickness. Taken together, these results indicated that BNE suppressed mast cell-mediated inflammation, suggesting that BNE might be a candidate for the treatment of various allergic disorders.

Invivo and invitro anti‑allergic and anti‑inflammatory effects of Dryopteriscrassirhizoma through the modulation of the NF‑ĸB signaling pathway in an ovalbumin‑induced allergic asthma mouse model.

Dryopteris crassirhizoma (DC) has a wide range of pharmacological effects, including antibacterial, anti-influenza virus, anti-tumor, anti-reverse transcriptase and antioxidant effects. However, the inhibitory effect of DC on allergic inflammatory response remains unclear; therefore, the current study used an experimental ovalbumin (OVA)-induced allergic asthma mouse model and phorbol myristate acetate (PMA)- and A23187-stimulated HMC-1 cells to reveal the effects of DC in regulating airway inflammation and its possible mechanism. Allergic asthma was initiated in BALB/c mice via exposure to OVA emulsified in aluminum, on days 1 and 14. Thereafter, the mice were treated with DC or dexamethasone (Dex) orally, before being challenged, from days 15 to 26. Subsequently, the mice were challenged with OVA on days 27, 28 and 29. The results of histological analysis indicated that the administration of DC decreased the number of inflammatory cells in the bronchoalveolar lavage fluid (BALF) and suppressed eosinophilic infiltration, mucus production and collagen deposition in the lung tissue. DC treatment increased the level of T helper type 1 (Th1) cytokines (IL-10 and interferon (IFN)-γ) and decreased the levels Th2 cytokines (IL-4, IL-5 and IL-13) and proinflammatory cytokines (IL-6 and TNF-α). Furthermore, DC treatment inhibited the activation of NF-κB signaling (NF-κB, p-NF-κB, IκB and p-IκB), both in BALF and lung homogenates. Serum levels of total IgE and OVA-specific IgE and IgG1 were significantly lower after DC treatment compared with after OVA treatment. However, the anti-inflammatory effect of OVA-specific IgG2a was higher after DC treatment. In addition, DC treatment attenuated the production of proinflammatory cytokines, including IL-6 and TNF-α, and the activation of NF-κB signaling (NF-κB and p-NF-κB), in PMA and calcium ionophore A23187-stimulated HMC-1 cells. In summary, the current study demonstrated that DC acts a potent anti-allergic and anti-inflammatory drug by modulating the Th1 and Th2 response and reducing the allergic inflammatory reaction in PMA and A23187-stimulated HMC-1 cells via NF-κB signaling in an OVA-induced allergic asthma model.

IL-37 relieves allergic inflammation by inhibiting the CCL11 signaling pathway in a mouse model of allergic rhinitis.

Allergic rhinitis (AR) is the allergic inflammation of immune cells in the nasal mucosa, caused by an abnormal T-cell response. Interleukin (IL)-37, a unique member of the IL-1 family with broad anti-inflammatory roles in various autoimmune diseases, participates in the immune regulation of AR. However, the regulatory mechanism of IL-37 in AR has remained elusive. In the present study, a mouse model of AR was established by treating mice with ovalbumin (OVA). Following systemic administration of IL-37, the effects of the cytokine on allergic symptoms were evaluated. The nasal mucosal infiltration of eosinophils was assessed by histopathological observation. The serum and nasal lavage fluid concentrations of immunoglobulin (Ig)E, IgG1, IgG2a, interferon (IFN)-γ, IL-4, IL-13, IL-17a and C-C motif cytokine ligand (CCL)11 were determined by ELISA. Treatment with OVA resulted in allergic symptoms, including enhanced eosinophil infiltration in the nasal mucosa, increased thickness of the nasal mucosa and increased levels of IgE, IgG1, IgG2a, IL-4, IL-13, IL-17a and CCL11, but the level of IFN-γ was indicated to decrease. After IL-37 treatment, the frequency of nasal rubbing and sneezing was reduced compared with that in the OVA group. IL-37 administration also decreased the number of eosinophils in the nasal mucosa and the thickness of the nasal mucosa, as well as the serum and nasal lavage fluid levels of IgE, IgG1, IgG2a, IL-4, IL-13, IL-17a and CCL11, but the level of IFN-γ decreased. In addition, the OVA-induced increases in histamine and substance P levels were reversed by IL-37 administration. CCL11 expression levels were correlated with the expression levels of IFN-γ, IL-4, IL-13, IL-17a, histamine and substance P. In conclusion, IL-37 alleviated the OVA-induced allergic symptoms and allergic inflammatory response by reducing the serum cytokine levels via decreasing CCL11 expression levels in mice.

Functional role of phosphatidylcholine-specific phospholipase C in regulating leukotriene synthesis and degranulation in human eosinophils

Phosphatidylinositol-specific phospholipase C (PI-PLC) and cytosolic phospholipase A2 (cPLA2) regulate both eosinophil degranulation and leukotriene (LT) synthesis via PI-PLC-mediated calcium influx and cPLA2 activation. Phosphatidylcholine-specific phospholipase C (PC-PLC) likely plays a key role in cellular signaling, including the eosinophilic allergic inflammatory response. This study examined the role of PC-PLC in eosinophil LT synthesis and degranulation using tricyclodecan-9-yl-xanthogenate (D609), a PC-specific PLC inhibitor. D609 inhibited N-formyl-met-leu-phe + cytochalasin B (fMLP/B)-induced arachidonic acid (AA) release and leukotriene C4 (LTC4) secretion. However, at concentrations that blocked both AA release and LTC4 secretion, D609 had no significant inhibitory effect on stimulated cPLA2 activity. D609 also partially blocked fMLP/B-induced calcium influx, indicating that inhibition of AA release and LTC4 secretion by D609 is due to inhibition of calcium-mediated cPLA2 translocation to intracellular membranes, not inhibition of cPLA2 activity. In addition, D609 inhibited fMLP/B-stimulated eosinophil peroxidase release, indicating that PC-PLC regulates fMLP/B-induced eosinophil degranulation by increasing the intracellular calcium concentration ([Ca2+]i). Overall, our results showed that PC-PLC is critical for fMLP/B-stimulated eosinophil LT synthesis and degranulation. In addition, degranulation requires calcium influx, while PC-PLC regulates LTC4 synthesis through calcium-mediated cPLA2 activation.

Chlorogenic Acid Alleviates Allergic Inflammatory Responses Through Regulating Th1/Th2 Balance in Ovalbumin-Induced Allergic Rhinitis Mice.

BackgroundAllergic rhinitis (AR) is a prevalent atopic disorder caused by immune imbalance. Chlorogenic acid (CGA) has antibacterial, antiviral, antioxidative and immunoregulatory effects, but its role in anaphylactic disease remains unclear. The current study aimed to investigate the function of CGA in AR.Material/MethodsAR mice models were induced with ovalbumin (OVA) by orally administrating the mice with 50 mg/kg (L-CGA), 100 mg/kg (M-CGA), or 200 mg/kg (H-CGA) of CGA. The number of nasal rubbings and sneezes was recorded. Afterward, the mice were sacrificed for the collection of blood, nasal lavage fluid (NALF), and nasal tissues. The cells in NALF were counted by hemocytometer and stained by Diff-Quick. Nasal mucosa was observed by H&E staining. ELISA testing was conducted for detecting the levels of anti-OVA antibodies and Th1/Th2-related cytokine. Quantitative real-time polymerase chain reaction experiments were conducted to determine mRNA expressions of Th1/Th2-related cytokines.ResultsIn the OVA-induced AR mice, CGA treatment reduced nasal rubbing and sneezing, and also suppressed the number of total cells, eosinophils, neutrophils, lymphocytes, macrophages, and epithelial cells in NALF. OVA-induced up-regulation of nasal mucosa thickness was inhibited by CGA, and the effects of OVA on IgE, IgG1, and IgG2a were reversed by CGA. The regulatory effects of OVA on mRNA expressions and levels of Th1/Th2-related cytokines were abolished by CGA treatment in AR mice.ConclusionsCGA can alleviate allergic inflammatory responses through regulating Th1/Th2 balance in OVA-induced allergic rhinitis mice.