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Mesenchymal stromal cells (MSCs) have long been considered a potential tool for treatment of allergic inflammatory diseases, owing to their immunomodulatory characteristics. In recent decades, the medical utility of MSCs has been evaluated both in vitro and in vivo, providing a foundation for therapeutic applications. However, the existing limitations of MSC therapy indicate the necessity for novel therapies. Notably, small extracellular vesicles (sEV) derived from MSCs have emerged rapidly as candidates instead of their parental cells. The acquisition of abundant and scalable MSC-sEV is an obstacle for clinical applications. The potential application of MSC-sEV in allergic diseases has attracted increasing attention from researchers. By carrying biological microRNAs or active proteins, MSC-sEV can modulate the function of various innate and adaptive immune cells. In this review, we summarise the recent advances in the immunomodulatory properties of MSCs in allergic diseases, the cellular sources of MSC-sEV, and the methods for obtaining high-quality human MSC-sEV. In addition, we discuss the immunoregulatory capacity of MSCs and MSC-sEV for the treatment of asthma, atopic dermatitis, and allergic rhinitis, with a special emphasis on their immunoregulatory effects and the underlying mechanisms of immune cell modulation., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

We previously identified an immunomodulatory role of human induced pluripotent stem cell (iPSC)-derived mesenchymal stem cells (MSCs) in asthmatic inflammation. Mitochondrial transfer from bone marrow MSCs to epithelial cells can result in the attenuation of acute lung injury in mice. However, the effects of mitochondrial transfer from iPSC-MSCs to epithelial cells in asthma and the mechanisms underlying these effects are unclear. We found that iPSC-MSC transplantation significantly reduced T helper 2 cytokines, attenuated the mitochondrial dysfunction of epithelial cells, and alleviated asthma inflammation in mice. Tunneling nanotubes (TNTs) were formed between iPSC-MSCs and epithelial cells, and mitochondrial transfer from iPSC-MSCs to epithelial cells via TNTs was observed both in vitro and in mice. Overexpression or silencing of connexin 43 (CX43) in iPSC-MSCs demonstrated that CX43 plays a critical role in the regulation of TNT formation by mediating mitochondrial transfer between iPSC-MSCs and epithelial cells. This study provides a therapeutic strategy for targeting asthma inflammation., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Asthma is affecting more than 300 million people worldwide, which represents the most common chronic disease among children. We previously found that mesenchymal stem cells (MSCs) derived from induced pluripotent stem cells (iPSCs) modulated the immune response on Th2-mediated asthma in vivo and in vitro. This study further evaluated the immunomodulatory effects of MSCs from human embryonic stem cells (hESCs) on asthma., Methods: Multipotent hESC-MSCs were obtained using a feeder-free method. The hESC-MSCs were analysed for the expression of stem cell surface markers by flow cytometry, their differentiation potentials were analysed using in vitro trilineage differentiation methods hESC-MSCs were transplanted into the murine model with ovalbumin (OVA)-induced airway allergic inflammation. The expression levels of allergic related genes were measured by the mRNA PCR arrays., Results: The hESC-MSCs expressed classical MSC markers and held the capability of differentiation into multiple mesoderm-type cell lineages. hESC-MSCs were able to suppress allergic inflammation by modulating Th2 cells and eosinophils in the mice, and reversed the reduction of regulatory T cells. By using PCR array, 5 mRNAs- chemokine (C-C motif) ligand 11 (Ccl11), Ccl24, interleukin13 (Il13), Il33 and eosinophil-associated, ribonuclease A family, member 11 (Ear11) were identified the most relevant in murine airway allergic inflammation and hESC-MSCs treatment., Conclusions: The therapeutic effects of hESC-MSCs were identified in the murine model of airway allergic inflammation with key mRNAs involved. This study will provide a better understanding regarding the mechanisms underlying hESC-MSCs therapeutic application in airway allergic inflammation., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The T helper 2 (Th2)-type response was considered the hypostasis of allergic airway diseases, including asthma and allergic rhinitis (AR). However, more recent studies have suggested that allergic airway inflammation also depends on innate immunity and is closely related to group 2 innate lymphoid cells (ILC2s). This study evaluated the ILC2 levels of asthma subjects, patients with asthma and AR, and healthy individuals, regarding how to investigate the relationship between clinical data and ILC2 levels. It was found that asthma patients and asthma with AR patients had higher ILC2 levels compared to healthy subjects. ILC2s were positively correlated with the percentage of eosinophils in patients with asthma and AR, but not with pulmonary function. ILC2 levels were higher in mild asthma subjects than in patients with severe asthma. This study provides a new interpretation of the pathogenesis of allergic airway inflammation and may provide a new direction for the diagnosis and assessment of allergic airway diseases., (© 2018 S. Karger AG, Basel.)

Allergic asthma is associated with airway inflammation and airway hyperresponsiveness. Macrophage polarization has been shown to have a profound impact on asthma pathogenesis. On exposure to local microenvironments, recruited macrophages can be polarized into either classically activated (or M1) or alternatively activated (or M2) phenotypes. Macrophage polarization has been heavily associated with development of asthma. The process of regulation of macrophage polarization involves an intricate interplay between various cytokines, chemokines, transcriptional factors, and immune-regulatory cells. Different signals from the microenvironment are controlled by different receptors on the macrophages to initiate various macrophage polarization pathways. Most importantly, there is an increased attention on the epigenetic changes (eg, microRNAs, DNA methylation, and histone modification) that impact macrophage functional responses and M1/M2 polarization through modulating cellular signaling and signature gene expression. Thus, modulation of macrophage phenotypes through molecular intervention by targeting some of those potential macrophage regulators may have therapeutic potential in the treatment of allergic asthma and other allergic diseases. In this review, we will discuss the origin of macrophages, characterization of macrophages, macrophage polarization in asthma, and the underlying mechanisms regarding allergen-induced macrophage polarization with emphasis on the regulation of epigenetics, which will provide new insights into the therapeutic strategy for asthma., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Asthma is one of the most common chronic diseases and associated with significant morbidity and mortality. However, few data on occupational and environmental risk factors of asthma are available, particularly in Asian adults. Based on a national cross-sectional survey, we assessed the prevalence and risk factors of asthma in Chinese adults., Methods: A total of 9974 participants aged 15 years and over in seven Chinese cities were selected using a stratified four-stage random sampling. All participants were interviewed face-to-face in their homes using a standardized self-administered questionnaire. Multivariate logistic regression analyses were adopted to determine various risk factors for asthma., Results: The prevalence of self-reported lifetime asthma was 2.46% among the entire adult population, 3.02% among males and 1.93% among females. The prevalence varied by age group, ethnicity, marital status, education, and floor space per person ( p < 0.05). After adjusting for socio-demographic variables and smoking, we found independent occupational and environmental determinants of asthma, including a clearance-related job (OR = 2.28, 95%CI: 1.07-4.89), occupational exposure to industrial or occupational poisonous gas (OR = 4.21, 95%CI: 2.43-7.30), having large amounts of carpet in the workplace (OR = 2.61, 95%CI: 1.20-5.69) and using coal for cooking (OR = 2.65, 95%CI: 1.26-5.57)., Conclusions: Asthma is a serious public health problem in China. Our study provides important updated information on the prevalence of asthma and its associated risk factors, which may help us better understand the epidemiology of asthma and prevent this disorder., Competing Interests: The authors declare no conflict of interests.

Administration of human bone marrow-derived mesenchymal stem cells (BM-MSCs) significantly alleviates allergic airway inflammation. There are no studies that refer to the role of microRNAs (miRNAs) after the BM-MSCs treatment in airway allergic inflammation. We induced a mouse model of asthma and performed the transplantation of BM-MSCs. We analyzed aberrant miRNAs and key immune regulators using both miRNA and messenger RNA (mRNA) polymerase chain reaction (PCR) arrays. We identified that 296 miRNAs were differently expressed after the induction of asthma and/or the treatment of BM-MSCs, in which 14 miRNAs presented the reverse variation tendency between asthma induction and BM-MSCs transplantation. Mmu-miR-21a-3p, mmu-miR-449c-5p, and mmu-miR-496a-3p were further confirmed to be differently expressed with additional samples and quantitative real-time PCR. With an mRNA PCR array, we identified 19 genes to be involved in the allergy induction and the administration of BM-MSCs. Further target genes analysis revealed that mmu-miR-21a-3p was significantly correlated with the immune regulator activin A receptor, Type IIA (Acvr2a). Mmu-miR-21a-3p had opposite expression with Acvr2a after asthma and BM-MSCs treatment. Acvr2a had binding sites for miR-21a for both mice and human, suggesting that miR-21/Acvr2a axis is conserved between human and mice. Dual-luciferase reporter assay showed that mmu-miR-21a-3p negatively regulated the transcript of Acvr2a. In addition, has-miR-21a inhibitor significantly increased the expression of Acvr2a mRNA in BEAS-2B cells under lipopolysaccharide stimulation. Our results suggest that there were different miRNA and mRNA profiles after asthma induction and BM-MSCs treatment, and the miR-21/Acvr2a axis is an important mechanism for the induction of asthmatic inflammation.

Background: Connexin (Cx)-based gap junction channels play important roles in the inflammatory response. Cx43 is involved in the pathogenesis of some lung diseases such as acute lung injury. However, the Cx43 expression in asthma is unclear. In the present study, we used a murine model of ovalbumin (OVA)-induced allergic airway disease to examine the levels of Cx43 and analyze the relationship between Cx43 and airway inflammation in allergic airway disease., Methods: Asthma was induced in mice via sensitization and challenge with OVA. Cx43 mRNA and protein expression levels were investigated via QT-PCR, western blot, and immunohistochemistry 0 h, 8 h, 1 d, 2 d and 4 d after the first challenge. The relationship between Cx43 protein levels and inflammatory cell infiltration, cytokine levels was analyzed., Results: The OVA-induced mice exhibited typical pathological features of asthma, including airway hyper-responsiveness; strong inflammatory cell infiltration surrounding the bronchia and vessels; many inflammatory cells in the bronchoalveolar lavage fluid (BALF); higher IL-4, IL-5 and IL-13 levels; and high OVA specific IgE levels. Low Cx43 expression was detected in the lungs of control (PBS) mice. A dramatic increase in the Cx43 mRNA and protein levels was found in the asthmatic mice. Cx43 mRNA and protein expression levels increased in a time-dependent manner in asthma mice, and Cx43 was mostly localized in the alveolar and bronchial epithelial layers. Moreover, lung Cx43 protein levels showed a significant positive correlation with inflammatory cell infiltration in the airway and IL-4 and IL-5 levels in the BALF at different time points after challenge. Interestingly, the increase in Cx43 mRNA and protein levels occurred prior to the appearance of the inflammatory cell infiltration., Conclusion: Our data suggest that there is a strong upregulation of Cx43 mRNA and protein levels in the lungs in asthma. Cx43 levels also exhibited a positive correlation with allergic airway inflammation. Cx43 may represent a target to treat allergic airway diseases in the future.

We previously found that mesenchymal stem cells (MSCs) derived from human-induced pluripotent stem cells (iPSCs) exerted immunomodulatory effects on Th2-mediated allergic rhinitis in vitro. However, their contribution to the asthma and allergic rhinitis in animal models remains unclear. In this study, we developed a mouse model of ovalbumin (OVA)-induced allergic inflammation in both the upper and lower airways and evaluated the effects of the systemic administration of human iPSC-MSCs and bone marrow-derived MSCs (BM-MSCs) on allergic inflammation. Our results showed that treatments with both the iPSC-MSCs and BM-MSCs before the challenge phase protected the animals from the majority of allergy-specific pathological changes. This protection included an inhibition of inflammatory cell infiltration and mucus production in the lung, a reduction in eosinophil infiltration in the nose, and a decrease in inflammatory cell infiltration in both the bronchoalveolar and nasal lavage fluids. In addition, treatment with iPSC-MSCs or BM-MSCs before the challenge phase resulted in reduced serum levels of Th2 immunoglobulins (e.g., IgE) and decreased levels of Th2 cytokines including interleukin (IL)-4, IL-5, or IL-13 in the bronchoalveolar and/or nasal lavage fluids. Similar therapeutic effects were observed when the animals were pretreated with human iPSC-MSCs before the sensitization phase. These data suggest that iPSC-MSCs may be used as an alternative strategy to adult MSCs in the treatment of asthma and allergic rhinitis., (Copyright © 2012 AlphaMed Press.)

Background: According to the hygiene hypothesis, bacterial infections during early life contribute to a reduced incidence of asthma in animals. However, the effects of microbial products at a safe dose and within a rational time course on the prevention of allergic rhinitis (AR) have been inconclusive. This study investigated the immunomodulatory effects of oral administration of a bacterial extract, OM-85 Broncho-Vaxom (BV), with a low dose and general time course, which is currently used for respiratory infections in humans, on AR inflammation in mice. Methods: We developed a mouse model of ovalbumin (OVA)-induced AR allergic inflammation in the nose mucosa of mice. Low doses of OM-85 BV were orally administered for 3 months (long term) before sensitization. We evaluated nasal symptoms, pathology in the nose, inflammatory cells, and the levels of T helper 1 (Th1)/Th2 cytokines in the nasal lavage fluids, and the serum levels of specific IgE and IgG1. We also observed enhanced effects of OM-85BV with 1 month (short term) of treatment. Results: We found that long-term pretreatment with OM-85 BV protected the mice from the majority of allergy-specific symptoms; specifically, OM-85 BV suppressed nasal symptoms, inhibited eosinophil infiltration in the nose, inhibited inflammatory infiltrates and the Th2 response by reducing cytokines (IL-4, IL-5, or IL-13) in the nasal lavage fluids, and reduced IgE and IgG1 levels. Furthermore, short-term treatment with OM-85 BV decreased the levels of Th2 cytokines and IgE. Conclusion: Taken together, our data suggested that OM-85 BV is a low-cost alternative candidate to prevent AR with simple oral administration. [ABSTRACT FROM AUTHOR]

• Female mice with ILC2-dominant allergic airway inflammation exhibited higher levels of ILC2 levels compared to male mice. • The treatment of testosterone significantly decreased the intracellular type 2 cytokines ILC2. • Testosterone suppressed the proliferation of ILC2s. There were gender differences in the prevalence and severity of allergic diseases. Group 2 innate lymphoid cells (ILC2s) were recently reported to play a critical role in allergic diseases. We investigated the sex-dependent differences in ILC2-dominant allergic airway inflammation model using T\B cell-deficient mice, and determined the gender differences of ILC2 levels in patients with asthma and allergic rhinitis. Female mice exhibited higher levels of inflammatory infiltration and large production of IL-5 and IL-13, especially for ILC2 levels compared to male mice with the induction of IL-33. However, no significant differences were found for the levels of circulating ILC2s between the genders of patients. The treatment of testosterone significantly decreased the intracellular type 2 cytokines in ILC2s and the proliferation of pure ILC2s in response to epithelial cytokines. Our study suggested the sex differences and the involvement of androgen on ILC2s in allergic diseases. [ABSTRACT FROM AUTHOR]