Combination of TLR agonist and miR146a mimics attenuates ovalbumin-induced asthma

Wang, Xinhua; Lu, Xiaoxian; Ma, Chenhui; Ma, Lihong; Han, Song

doi:10.1186/s10020-020-00191-1

Cited by 16 publications

(7 citation statements)

References 25 publications

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“…MiRNAs are potential candidates for asthma therapy. For example, miR-146a-5p was reported to efficiently protect mice against OVA-induced allergic asthma ( 32 , 33 ), and also modulate anti-fibrosis responses ( 34 ). Thus, the anti-asthma effects of miR-146a-5p-EVs (Hypo-EVs carrying miR-146a-5p) might be more profound than those of Hypo-EVs.…”

Section: Resultsmentioning

confidence: 99%

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

Wang

Luo

et al. 2023

Front. Immunol.

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Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) are extremely promising nanoscale cell-free therapeutic agents. We previously identified that intravenous administration (IV) of human umbilical cord MSC-EVs (hUCMSC-EVs), especially hypoxic hUCMSC-EVs (Hypo-EVs), could suppress allergic airway inflammation and remodeling. Here, we further investigated the therapeutic effects of Hypo-EVs administration by atomizing inhalation (INH), which is a non-invasive and efficient drug delivery method for lung diseases. We found that nebulized Hypo-EVs produced by the atomization system (medical/household air compressor and nebulizer) maintained excellent structural integrity. Nebulized Dir-labeled Hypo-EVs inhaled by mice were mainly restricted to lungs. INH administration of Hypo-EVs significantly reduced the airway inflammatory infiltration, decreased the levels of IL-4, IL-5 and IL-13 in bronchoalveolar lavage fluid (BALF), declined the content of OVA-specific IgE in serum, attenuated the goblet cell metaplasia, and the expressions of subepithelial collagen-1 and α-smooth muscle actin (α-SMA). Notably, Hypo-EV INH administration was generally more potent than Hypo-EV IV in suppressing IL-13 levels and collagen-1 and α-SMA expressions. RNA sequencing revealed that various biological processes, such as cell adhesion, innate immune response, B cell activation, and extracellular space, were associated with the activity of Hypo-EV INH against asthma mice. In addition, Hypo-EVs could load exogenous miR-146a-5p (miR-146a-5p-EVs). Furthermore, INH administration of miR-146a-5p-EVs resulted in a significantly increased expression of miR-146a-5p mostly in lungs, and offered greater protection against the OVA-induced increase in airway inflammation, subepithelial collagen accumulation and myofibroblast compared with nebulized Hypo-EVs. Overall, nebulized Hypo-EVs effectively attenuated allergic airway inflammation and remodeling, potentially creating a non-invasive route for the use of MSC-EVs in asthma treatment.

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Section: Resultsmentioning

confidence: 99%

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

Wang

Luo

et al. 2023

Front. Immunol.

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“…It has been reported that hypoxia culture enhances the anti-inflammatory potency of MSCs in OVA mouse, and miR-146a-5p is critical for these properties [ 18 ]. Apart from modulating anti-inflammatory responses [ 34 , 35 ], miR-146a-5p also has the effect of inhibiting TGF-β1-Smad signaling [ 36 ]. After hUCMSCs were exposed to hypoxia for 24 h, the expression of HIF-1α was increased compared with that of hUCMSC cultured in normoxia (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In recent years, miRNAs have been shown to be an important beneficial mechanism in the immune microenvironment. Especially, it has been reported that miR-146a-5p could inhibit the proliferation and function (IL-13 secretion) of type II innate lymphoid cells (ILC2), efficiently protect mice against OVA-induced allergic asthma [ 34 , 35 ], and also modulate anti-fibrosis responses induced by TGF-β1-Smad signaling [ 36 ]. The content of miR-146a-5p is relatively abundant in hUCMSC-EVs in accordance with a previous study [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice

et al. 2021

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Background As one of the main functional forms of mesenchymal stem cells (MSCs), MSC-derived extracellular vesicles (MSC-EVs) have shown an alternative therapeutic option in experimental models of allergic asthma. Oxygen concentration plays an important role in the self-renewal, proliferation, and EV release of MSCs and a recent study found that the anti-asthma effect of MSCs was enhanced by culture in hypoxic conditions. However, the potential of hypoxic MSC-derived EVs (Hypo-EVs) in asthma is still unknown. Methods BALB/c female mice were sensitized and challenged with ovalbumin (OVA), and each group received PBS, normoxic human umbilical cord MSC-EVs (Nor-EVs), or Hypo-EVs weekly. After treatment, the animals were euthanized, and their lungs and bronchoalveolar lavage fluid (BALF) were collected. With the use of hematoxylin and eosin (HE), periodic acid-Schiff (PAS) and Masson’s trichrome staining, enzyme-linked immune sorbent assay (ELISA), Western blot analysis, and real-time PCR, the inflammation and collagen fiber content of airways and lung parenchyma were investigated. Results Hypoxic environment can promote human umbilical cord MSCs (hUCMSCs) to release more EVs. In OVA animals, the administration of Nor-EVs or Hypo-EVs significantly ameliorated the BALF total cells, eosinophils, and pro-inflammatory mediators (IL-4 and IL-13) in asthmatic mice. Moreover, Hypo-EVs were generally more potent than Nor-EVs in suppressing airway inflammation in asthmatic mice. Compared with Nor-EVs, Hypo-EVs further prevented mouse chronic allergic airway remodeling, concomitant with the decreased expression of pro-fibrogenic markers α-smooth muscle actin (α-SMA), collagen-1, and TGF-β1-p-smad2/3 signaling pathway. In vitro, Hypo-EVs decreased the expression of p-smad2/3, α-SMA, and collagen-1 in HLF-1 cells (human lung fibroblasts) stimulated by TGF-β1. In addition, we showed that miR-146a-5p was enriched in Hypo-EVs compared with that in Nor-EVs, and Hypo-EV administration unregulated the miR-146a-5p expression both in asthma mice lung tissues and in TGF-β1-treated HLF-1. More importantly, decreased miR-146a-5p expression in Hypo-EVs impaired Hypo-EV-mediated lung protection in OVA mice. Conclusion Our findings provided the first evidence that hypoxic hUCMSC-derived EVs attenuated allergic airway inflammation and airway remodeling in chronic asthma mice, potentially creating new avenues for the treatment of asthma.

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“…Several studies have identi ed aberrant miRNA expression pro les associated with asthma severity [9] , or therapy responses [10][11][12] . As a miRNA target gene, LIGHT may be regulated by miR-512-3p, miR-513b-5p, miR-5691, miR-107, miR-140-5p, and miR-17-5p screened by TargetScan.…”

Section: Disscussionmentioning

confidence: 99%

Circulating miRNAs targeting LIGHT as potential biomarkers for asthma

Chen

et al. 2023

Preprint

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Identification of new clinical markers contributes to a better understanding of the pathogenesis of asthma. Considering the crucial role of LIGHT in asthma, it may become a potential target for asthma. The aim of current study was to determine if circulating microRNAs (miRNAs) targeting LIGHT may be used as diagnostic biomarkers to distinguish asthma. Blood serum from a cohort of 60 subjects, including 20 cases with mild asthma, 20 cases with moderate-to-severe asthma, and 20 healthy controls were included. Serum was analyzed for circulating miRNAs profiles through miRNAs microarray. Real Time PCR was conducted to verify the results of miRNA microarray. Correlations between circulating miRNAs targeting LIGHT and clinical characteristics were investigated. A total of 365 miRNAs were differentially expressed in asthma patients. Among them, miR-107 and miR-140-5p were found to target LIGHT, and varied in asthmatics.Additionally, miR-107 and miR-140-5p expressions were positively correlated with the absolute value of peripheral eosinophils. Finally, miR-140-5p and miR-107 were demonstrated to have good diagnostic efficacy for asthma (AUC= 0.867 and 0.940) with good sensitivity (0.800 and 0.867 separately) and specificity (0.867 and 0.867). Thus, circulating miRNAs expressed differentially between healthy control and asthma patients. Plasma miR-140-5p and miR-107 can be used as diagnostic biomarkers to distinguish patients with asthma from healthy control, and may take part in asthma pathogenesis by negatively regulating LIGHT. Further research was needed to evaluate their roles as potential biomarkers in the diagnosis of asthma.

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Combination of TLR agonist and miR146a mimics attenuates ovalbumin-induced asthma

Cited by 16 publications

References 25 publications

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

A non-invasive strategy for suppressing asthmatic airway inflammation and remodeling: Inhalation of nebulized hypoxic hUCMSC-derived extracellular vesicles

Hypoxic hUCMSC-derived extracellular vesicles attenuate allergic airway inflammation and airway remodeling in chronic asthma mice

Circulating miRNAs targeting LIGHT as potential biomarkers for asthma

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