Background Although lung macrophages are directly exposed to external stimuli, their exact immunologic roles in asthma are still largely unknown. The aim of this study was to investigate the anti‐asthmatic effect of Acinetobacter lwoffii in terms of lung macrophage modulation. Methods Six‐week‐old female BALB/c mice were sensitized and challenged with ovalbumin (OVA) with or without intranasal administration of A. lwoffii during the sensitization period. Airway hyperresponsiveness and inflammation were evaluated. Using flow cytometry, macrophages were subclassified according to their activation status. In the in vitro study, a murine alveolar macrophage cell line (MH‐S) treated with or without A. lwoffii before IL‐13 stimulation were analysed by quantitative RT‐PCR. Results In a murine asthma model, the number of inflammatory cells, including macrophages and eosinophils, decreased in mice treated with A. lwoffii (A. lwoffii/OVA group) compared with untreated mice (OVA group). The enhanced expression of MHCII in macrophages in the OVA group was decreased by A. lwoffii treatment. M2 macrophage subtypes were significantly altered. A. lwoffii treatment decreased CD11b+M2a and CD11b+M2c macrophages, which showed strong positive correlations with Th2 cells, ILC2 and eosinophils. In contrast, CD11b+M2b macrophages were significantly increased by A. lwoffii treatment and showed strong positive correlations with ILC1 and ILC3. In vitro, A. lwoffii down‐regulated the expression of M2 markers related but up‐regulated those related to M2b macrophages. Conclusions and Clinical Relevance Intranasal A. lwoffii exposure suppresses asthma development by suppressing the type 2 response via modulating lung macrophage activation, shifting M2a and M2c macrophages to M2b macrophages.
Mesenchymal stem cells (MSCs) possess immunomodulatory properties that have therapeutic potential for the treatment of inflammatory diseases. This study investigates the effects of direct MSC administration on asthmatic airways. Umbilical cord MSCs (ucMSCs) were intratracheally administered to six-week-old female BALB/c mice sensitized and challenged with ovalbumin; airway hyperresponsiveness (AHR), analyses of airway inflammatory cells, lung histology, flow cytometry, and quantitative real-time PCR were performed. Furthermore, ex vivo and in vitro experiments were performed to assess the effects of ucMSC on M2 activation. Intratracheally administered ucMSCs decreased degree of airway resistance and the number of inflammatory cells such as T helper 2 (Th2) cells, type 2 innate lymphoid cells (ILC2), and macrophages in the murine asthma model. Particularly, MHCII and CD86 expression diminished in dendritic cells and alveolar macrophages (AMs) following ucMSC treatment. SiglecF+CD11c+CD11b- AMs show a negative correlation with type II inflammatory cells including Th2 cells, ILC2, and eosinophils in asthmatic mice and were restored following intratracheal ucMSCs treatment. In addition, ucMSCs decreased the macrophage polarization to M2, particularly M2a. The expression levels of markers associated with M2 polarization and Th2 inflammation were also decreased. ucMSC reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla ex vivo. Furthermore, the in vitro study using IL-4 treated macrophages confirmed that both direct and indirect MSC treatment significantly reduced the expression of Il-5 and Il-13. In conclusion, ucMSCs appear to suppress type II inflammation by regulating lung macrophages via soluble mediators.
The coronavirus disease 2019 (COVID-19) pandemic has threatened the stability of global healthcare, which is becoming an endemic issue. Despite the development of various treatment strategies to fight COVID-19, the currently available treatment options have shown varied efficacy. Herein, we have developed an avidity-based SARS-CoV-2 antagonist using dendrimer-peptide conjugates (DPCs) for effective COVID-19 treatment. Two different peptide fragments obtained from angiotensin-converting enzyme 2 (ACE2) were integrated into a single sequence, followed by the conjugation to poly(amidoamine) (PAMAM) dendrimers. We hypothesized that the strong multivalent binding avidity endowed by dendrimers would help peptides effectively block the interaction between SARS-CoV-2 and ACE2, and this antagonist effect would be dependent upon the generation (size) of the dendrimers. To assess this, binding kinetics of the DPCs prepared from generation 4 (G4) and G7 PAMAM dendrimers to spike protein of SARS-CoV-2 were quantitatively measured using surface plasmon resonance. The larger dendrimer-based DPCs exhibited significantly enhanced binding strength by 3 orders of magnitude compared to the free peptides, whereas the smaller one showed a 12.8-fold increase only. An in vitro assay using SARS-CoV-2-mimicking microbeads also showed the improved SARS-CoV-2 blockade efficiency of the G7-peptide conjugates compared to G4. In addition, the interaction between the DPCs and SARS-CoV-2 was analyzed using molecular dynamics (MD) simulation, providing an insight into how the dendrimer-mediated multivalent binding effect can enhance the SARS-CoV-2 blockade. Our findings demonstrate that the DPCs having strong binding to SARS-CoV-2 effectively block the interaction between ACE2 and SARS-CoV-2, providing a potential as a high-affinity drug delivery system to direct anti-COVID payloads to the virus.
BackgroundMesenchymal stem cells (MSCs) possess immunomodulatory properties that provide therapeutic potential for the treatment of inflammatory diseases. While the therapeutic and clinical effects of MSCs are partially known, the effects of its administration to the airway in asthma, a chronic airway inflammatory disease, remain unclear.MethodsSix-week-old female BALB/c mice were sensitized and challenged with ovalbumin. The effects of intratracheally administered umbilical cord MSCs were evaluated by measuring airway hyperresponsiveness, airway inflammatory cell analysis, histological analysis, flow cytometry, and quantitative real-time PCR. Furthermore, ex vivo experiments confirmed the effect of MSC treatment on macrophages that originated from bronchoalveolar lavage fluid and were treated with interleukin (IL)-4 to induce M2 activation. Additionally, an in vitro transwell assay confirmed the effect of MSCs on macrophage activation through direct or indirect treatment using the CRL-2019 alveolar macrophage (AM) cell line.ResultsIntratracheal administration of MSCs significantly decreased the elevated levels of inflammatory cells and airway resistance in the murine asthma model. MSC administration also significantly decreased the numbers of Th2 cells, ILC2, and macrophages in the lungs of asthmatic mice. In particular, MHCII and CD86 expression was prominently reduced in dendritic cells and AMs following MSC treatment. Suppressed SiglecF+CD11c+CD11b- resident AMs, presenting strong negative correlation with type II inflammatory cells such as Th2 cells, ILC2, and eosinophils, were restored by intratracheal MSC treatment. Typical macrophage polarization to M2, particularly M2a, was significantly diminished. Expression levels of markers presenting M2 polarization and Th2 inflammation were decreased in the asthma model upon MSC administration. Ex vivo experiments of IL-4 treated AMs confirmed that MSC treatment reduced Il-12 and Tnfa expression as well as that of M2 markers such as Cd206 and Retnla. In vitro experiments of IL-4 treated AMs confirmed that both direct and indirect MSC treatments through transwells significantly reduced Il-5 and Il-13 expression. No difference between the two treatment methods was found.ConclusionsUmbilical cord MSCs appear to regulate pulmonary macrophages, suppress Th2 inflammation, and mediate anti-asthmatic effects via soluble mediators.
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