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A Phosphatase-Mimetic Nano-Stabilizer of Mast Cells for Long-Term Prevention of Allergic Disease.

ABSTRACT: Allergic diseases are pathological immune responses with significant morbidity, which are closely associated with allergic mediators as released by allergen-stimulated mast cells (MCs). Prophylactic stabilization of MCs is regarded as a practical approach to prevent allergic diseases. However, most of the existing small molecular MC stabilizers exhibit a narrow therapeutic time window, failing to provide long-term prevention of allergic diseases. Herein, ceria nanoparticle (CeNP-) based phosphatase-mimetic nano-stabilizers (PMNSs) with a long-term therapeutic time window are developed for allergic disease prevention. By virtue of the regenerable catalytic hotspots of oxygen vacancies on the surface of CeNPs, PMNSs exhibit sustainable phosphatase-mimetic activity to dephosphorylate phosphoproteins in allergen-stimulated MCs. Consequently, PMNSs constantly modulate intracellular phospho-signaling cascades of MCs to inhibit the degranulation of allergic mediators, which prevents the initiation of allergic mediator-associated pathological responses, eventually providing protection against allergic diseases with a long-term therapeutic time window.

SUBMITTER: Lin P

PROVIDER: S-EPMC8061383 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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A Phosphatase-Mimetic Nano-Stabilizer of Mast Cells for Long-Term Prevention of Allergic Disease.

Lin Peihua P Cao Mengda M Xia Fan F Liao Hongwei H Sun Heng H Wang Qiyue Q Lee Jiyoung J Zhou Yan Y Guan Yunan Y Zhang Cheng C Xu Zhiqiang Z Li Fangyuan F Wei Ji-Fu JF Ling Daishun D

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20210208 8

Allergic diseases are pathological immune responses with significant morbidity, which are closely associated with allergic mediators as released by allergen-stimulated mast cells (MCs). Prophylactic stabilization of MCs is regarded as a practical approach to prevent allergic diseases. However, most of the existing small molecular MC stabilizers exhibit a narrow therapeutic time window, failing to provide long-term prevention of allergic diseases. Herein, ceria nanoparticle (CeNP-) based phosphat ...[more]

PMID: 33898190

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Project description:BackgroundAllergic respiratory diseases have increased dramatically due to air pollution over the past few decades. However, studies are limited on the effects of inorganic components and particulate matter with different particle sizes in smog on allergic diseases, and the possible molecular mechanism of inducing allergies has not been thoroughly studied.MethodsFour common mineral elements with different particle sizes in smog particles were selected, including Al2O3, TiO2, Fe2O3, and SiO2. We studied the relationship and molecular mechanism of smog particle composition, particle size, and allergic reactions using mast cells, immunoglobulin E (IgE)-mediated passive cutaneous anaphylaxis (PCA) model, and an ovalbumin (OVA)-induced asthmatic mouse model in vitro and in vivo, combined with transmission electron microscopy, scanning transmission X-ray microscopy analysis, and transcriptome sequencing.ResultsOnly 20 nm SiO2 particles significantly increased β-hexosaminidase release, based on dinitrophenol (DNP)-human serum albumin (HSA) stimulation, from IgE-sensitized mast cells, while other particles did not. Meanwhile, the PCA model showed that Evan's blue extravasation in mice was increased after treatment with nano-SiO2 particles. Nano-SiO2 particles exposure in the asthmatic mouse model caused an enhancement of allergic airway inflammation as manifested by OVA-specific serum IgE, airway hyperresponsiveness, lung inflammation injury, mucous cell metaplasia, cytokine expression, mast cell activation, and histamine secretion, which were significantly increased. Nano-SiO2 particles exposure did not affect the expression of FcϵRI or the ability of mast cells to bind IgE but synergistically activated mast cells by enhancing the mitogen-activated protein kinase (MAPK) signaling pathway, especially the phosphorylation levels of the extracellular signal-regulated kinase (ERK)1/2. The ERK inhibitors showed a significant inhibitory effect in reducing β-hexosaminidase release.ConclusionOur results indicated that nano-SiO2 particles stimulation might synergistically activate IgE-sensitized mast cells by enhancing the MAPK signaling pathway and that nano-SiO2 particles exposure could exacerbate allergic inflammation. Our experimental results provide useful information for preventing and treating allergic diseases.

Project description:Atopic dermatitis is a chronic inflammatory skin disease that affects 15-30% of children and approximately 5% of adults in industrialized countries. Although the pathogenesis of atopic dermatitis is not fully understood, the disease is mediated by an abnormal immunoglobulin-E immune response in the setting of skin barrier dysfunction. Mast cells contribute to immunoglobulin-E-mediated allergic disorders including atopic dermatitis. Upon activation, mast cells release their membrane-bound cytosolic granules leading to the release of several molecules that are important in the pathogenesis of atopic dermatitis and host defence. More than 90% of patients with atopic dermatitis are colonized with Staphylococcus aureus in the lesional skin whereas most healthy individuals do not harbour the pathogen. Several staphylococcal exotoxins can act as superantigens and/or antigens in models of atopic dermatitis. However, the role of these staphylococcal exotoxins in disease pathogenesis remains unclear. Here we report that culture supernatants of S. aureus contain potent mast-cell degranulation activity. Biochemical analysis identified δ-toxin as the mast cell degranulation-inducing factor produced by S. aureus. Mast cell degranulation induced by δ-toxin depended on phosphoinositide 3-kinase and calcium (Ca(2+)) influx; however, unlike that mediated by immunoglobulin-E crosslinking, it did not require the spleen tyrosine kinase. In addition, immunoglobulin-E enhanced δ-toxin-induced mast cell degranulation in the absence of antigen. Furthermore, S. aureus isolates recovered from patients with atopic dermatitis produced large amounts of δ-toxin. Skin colonization with S. aureus, but not a mutant deficient in δ-toxin, promoted immunoglobulin-E and interleukin-4 production, as well as inflammatory skin disease. Furthermore, enhancement of immunoglobulin-E production and dermatitis by δ-toxin was abrogated in Kit(W-sh/W-sh) mast-cell-deficient mice and restored by mast cell reconstitution. These studies identify δ-toxin as a potent inducer of mast cell degranulation and suggest a mechanistic link between S. aureus colonization and allergic skin disease.

Project description:ObjectiveThe Centers for Medicare and Medicaid Services' National Partnership to Improve Dementia Care in Nursing Homes focuses on but is not limited to long-term care (LTC) residents with dementia; the potential impact on residents with other diagnoses is unclear. We sought to determine whether resident subpopulations experienced changes in antipsychotic and mood stabilizer prescribing.DesignRepeated cross-sectional analysis of a 20% Medicare sample, 2011-2014.Setting and participantFee-for-service Medicare beneficiaries with Part D coverage in LTC (n = 562,485) and a secondary analysis limited to persons with depression or bipolar disorder (n = 139,071).MethodsMain outcome was quarterly predicted probability of treatment with an antipsychotic or mood stabilizer.ResultsFrom 2011 to 2014, the adjusted predicted probability (APP) of antipsychotic treatment fell from 0.120 [95% confidence interval (CI) 0.119-0.121] to 0.100 (95% CI 0.099-0.101; P < .001). Use decreased for all age, sex, and racial/ethnic groups; the decline was larger for persons with dementia (P < .001). The APP of mood stabilizer use grew from 0.140 (95% CI 0.139-0.141) to 0.185 (95% CI 0.184-0.186), growth slightly larger among persons without dementia (P < .001). Among persons with depression or bipolar disorder, the APP of antipsychotic treatment increased from 0.081 (95% CI 0.079-0.082) to 0.087 (95% CI 0.085-0.088; P < .001); APP of mood stabilizer treatment grew more, from 0.193 (95% CI 0.190-0.196) to 0.251 (0.248-0.253; P < .001). Quetiapine was the most commonly prescribed antipsychotic. The most widely prescribed mood stabilizer was gabapentin, prescribed to 70.5% of those who received a mood stabilizer by the end of 2014.Conclusions and implicationsThe likelihood of antipsychotic and mood stabilizer treatment did not decline for residents with depression or bipolar disorder, for whom such prescribing may be appropriate but who were not excluded from the Partnership's antipsychotic quality measure. Growth in mood stabilizer use was widespread, and largely driven by growth in gabapentin prescribing.

Dataset Information

A Phosphatase-Mimetic Nano-Stabilizer of Mast Cells for Long-Term Prevention of Allergic Disease.

Publications

A Phosphatase-Mimetic Nano-Stabilizer of Mast Cells for Long-Term Prevention of Allergic Disease.

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