Allergic Airway Inflammation Responses Research Articles

Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function.

The role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia-inducible factor-1α (HIF-1α)-mediated glycolysis in ILC2-mediated allergic airway inflammation remain unclear. To investigate the role of the HIF-1α/glycolysis axis in ILC2-mediated allergic airway inflammation. Glycolysis and HIF-1α inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s invivo and vitro. Blocking glycolysis and HIF-1α in mice under interleukin-33 (IL-33) stimulation were performed to test ILC2 responses. Conditional HIF-1α-deficient mice were used to confirm the specific role of HIF-1α in ILC2-driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism. HIF-1α is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single-cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis-related genes, particularly HIF-1α, in murine lung ILC2s after IL-33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the HIF-1α inhibitor 2-methoxyestradiol (2-ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF-1α-deficient mice showed reduced ILC2 response and airway inflammation induced upon IL-33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF-1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis-related genes in HIF-1α-knockout and 2-DG-treated mice. Furthermore, impaired HIF-1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma. The HIF-1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.

The mouse model of chronic asthma: Airway remodelling and disease exacerbation by somatic antigen of Echinococcus granulosus.

There is now sufficient evidence to support an inverse association between helminth infection and secreted products with allergic/autoimmune disorders. Accordingly, several experimental studies have shown that Echinococcus granulosus infection and hydatid cyst compounds are able to suppress immune responses in allergic airway inflammation. This is the first study on effects of somatic antigens of E. granulosus on chronic allergic airway inflammation in BALB/c mice. Mice in OVA group were intraperitoneally (IP) sensitized with OVA/Alum. Subsequently, were challenged by nebulizing of OVA 1%. The treatment groups received somatic antigens of protoscoleces on the specified days. Mice in PBS group were received PBS in both sensitization and challenge. The effects of somatic products on development of chronic allergic airway inflammation were evaluated by examining histopathological changes, the recruitment of inflammatory cells in the bronchoalveolar lavage, cytokines production in the homogenized lung tissue, and total antioxidant capacity in serum. Our findings show that the co-administration of somatic antigens of protoscoleces simultaneously with the development of asthma intensifies allergic airway inflammation. The identification of effective components involved in exacerbation of allergic airway inflammation manifestations will be a crucial approach to understanding the mechanism of these interactions.

Dopamine inhibits group 2 innate lymphoid cell-driven allergic lung inflammation by dampening mitochondrial activity

Neuronal signals have emerged as pivotal regulators of group 2 innate lymphoid cells (ILC2s) that regulate tissue homeostasis and allergic inflammation. The molecular pathways underlying the neuronal regulation of ILC2 responses in lungs remain to be fully elucidated. Here, we found that the abundance of neurotransmitter dopamine was negatively correlated with circulating ILC2 numbers and positively associated with pulmonary function in humans. Dopamine potently suppressed lung ILC2 responses in a DRD1-receptor-dependent manner. Genetic deletion of Drd1 or local ablation of dopaminergic neurons augmented ILC2 responses and allergic lung inflammation. Transcriptome and metabolic analyses revealed that dopamine impaired the mitochondrial oxidative phosphorylation (OXPHOS) pathway in ILC2s. Augmentation of OXPHOS activity with oltipraz antagonized the inhibitory effect of dopamine. Local administration of dopamine alleviated allergen-induced ILC2 responses and airway inflammation. These findings demonstrate that dopamine represents an inhibitory regulator of ILC2 responses in allergic airway inflammation.

Exacerbation of allergic asthma by somatic antigen of Echinococcus granulosus in allergic airway inflammation in BALB/c mice

BackgroundThere is ample evidence demonstrating a reverse relationship between helminth infection and immune-mediated diseases. Accordingly, several studies have shown that Echinococcus granulosus infection and hydatid cyst compounds are able to suppress immune responses in allergic airway inflammation. Previous studies have documented the ability of hydatid cysts to suppress aberrant Th2 immune response in a mouse model of allergic asthma. However, there is a paucity of research on the effects of protoscoleces on allergic asthma. Thus, this study was designed to evaluate the effects of somatic antigens of protoscoleces in a murine model of allergic airway inflammation.MethodsOvalbumin (OVA)/aluminum hydroxide (alum) was injected intraperitoneally to sensitize BALB/c mice over a period of 0 to 7 days, followed by challenge with 1% OVA. The treatment group received somatic antigens of protoscoleces emulsified with PBS on these days in each sensitization before being challenged with 1% OVA on days 14, 15, and 16. The effects of somatic antigens of protoscoleces on allergic airway inflammation were evaluated by examining histopathological changes, the recruitment of inflammatory cells in the bronchoalveolar lavage, cytokine production in the homogenized lung tissue (IL-4, IL-5, IL-10, IL-17, and IFN-γ), and total antioxidant capacity in serum.ResultsOverall, administration of somatic antigens of protoscoleces exacerbated allergic airway inflammation via increased Th2 cytokine levels in the lung homogenate, recruitment of eosinophils into bronchoalveolar lavage fluid, and pathological changes. In addition, total antioxidant capacity and IFN-γ levels declined following the administration of somatic antigens.ConclusionsThe results revealed that the co-administration of somatic products of protoscoleces with OVA/alum contributed to the exacerbation of allergic airway inflammation in BALB/c mice. Currently, the main cause of allergic-type inflammation exacerbation is unknown, and further research is needed to understand the mechanism of these interactions.Graphical

Pro-lymphangiogenic VEGFR-3 signaling modulates memory T cell responses in allergic airway inflammation.

In allergic airway inflammation, VEGFR-3-mediated lymphangiogenesis occurs in humans and mouse models, yet its immunological roles, particularly in adaptive immunity, are poorly understood. Here, we explored how pro-lymphangiogenic signaling affects the allergic response to house dust mite (HDM). In the acute inflammatory phase, the lungs of mice treated with blocking antibodies against VEGFR-3 (mF4-31C1) displayed less inflammation overall, with dramatically reduced innate and T cell numbers and reduced inflammatory chemokine levels. However, when inflammation was allowed to resolve and memory recall was induced 2 months later, mice treated with mF4-31C1 as well as VEGF-C/-D knockout models showed exacerbated type 2 memory response to HDM, with increased Th2 cells, eosinophils, type 2 chemokines, and pathological inflammation scores. This was associated with lower CCL21 and decreased TRegs in the lymph nodes. Together, our data imply that VEGFR-3 activation in allergic airways both help initiate the acute inflammatory response as well as regulate the adaptive (memory) response, possibly in part by shifting the TReg/Th2 balance. This introduces new immunomodulatory roles for pro-lymphangiogenic VEGFR-3 signaling in allergic airway inflammation and suggests that airway lymphatics may be a novel target for treating allergic responses.

Dendritic Cell-Restricted Progenitors Contribute to Obesity-Associated Airway Inflammation via Adam17-p38 MAPK-Dependent Pathway.

Proliferation of dendritic cell (DC)—restricted progenitor cells in bone marrow compartment is tightly regulated at steady state and responds to multiple tissue-specific triggers during disturbed homeostasis such as obesity. DCs in the lung stem from a rapidly dividing DC-restricted progenitor cells and are effective at generating adaptive immune responses in allergic airway inflammation. Precisely, how DC-restricted progenitor expansion and differentiation are influenced by airway inflammation to maintain constant supply of myeloid DCs is poorly understood. Here we show that a high fat diet (HFD) induces oxidative stress and accelerates the expansion of DC- restricted progenitor cells in bone marrow and correlates with persistent induction of p38 mitogen activated protein kinase (MAPK), which is blocked with a selective p38α/β MAPK inhibitor. Mice fed a HFD and sensitized to inhaled allergen house dust mite (HDM) led to alterations of DC- restricted progenitor cells that were characterized by increased expansion and seeding of lung DCs in airway inflammation. Mechanistically, we establish that the expansion induced by HFD dysregulates the expression of a disintegrin and metallopeptidase domain 17 (Adam17) and is required for p38 MAPK activation in DC-restricted progenitors. These results demonstrates that obesity produces persistent changes in DC precursors and that elevation of Adam17 expression is tightly coupled to p38 MAPK and is a key driver of proliferation. Altogether, these data provide phenotypic and mechanistic insight into dendritic cell supply chain in obesity-associated airway inflammation.

SPA0355 suppresses T-cell responses and reduces airway inflammation in mice

In recent studies, SPA0355, a thiourea analog, has been demonstrated to possess strong anti-inflammatory activity. However, the mechanisms underlying the effects of SPA0355 on immune-mediated diseases have not been fully defined. The present study was designed to investigate the immunological and molecular mechanisms by which SPA0355 modulates cluster of differentiation of (CD4)+ T-cell-mediated immune responses in allergic airway inflammation. In vitro studies have shown that SPA0355 suppresses CD4+ T-cell activation, proliferation, and differentiation via modulation of T-cell receptor (TCR) signal transduction and cytokine-induced Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling. Next, we investigated the efficacy of SPA0355 in ovalbumin (OVA)-induced allergic airway inflammation. Intraperitoneal administration of SPA0355 inhibited inflammatory cell recruitment into the airways as well as the production of Th2 cytokines in bronchoalveolar fluid and suppressed OVA-induced IgE production in serum. Additionally, SPA0355 suppressed mucin production and smooth muscle hypertrophy and prevented the development of airway hyperresponsiveness. Given that allergic airway inflammation is mainly driven by Th2 cell responses, it is highly possible that the defects in CD4+ T-cell activation and Th2 cell differentiation in the draining lymph nodes and suppressed NF-κB activation in the lungs of SPA0355-treated mice illustrate an immunological mechanism of the preventive effect of SPA0355 on the aforementioned asthmatic characteristics. Collectively, our results suggest that SPA0355 directly modulates Th1 and Th2 responses through the suppression of multiple signaling pathways triggered by TCR or cytokine receptor stimulation, and that SPA0355 has protective effects in a murine model of allergic airway inflammation.

Schistosoma mansoni-Mediated Suppression of Allergic Airway Inflammation Requires Patency and Foxp3+ Treg Cells

The continual rise of asthma in industrialised countries stands in strong contrast to the situation in developing lands. According to the modified Hygiene Hypothesis, helminths play a major role in suppressing bystander immune responses to allergens, and both epidemiological and experimental studies suggest that the tropical parasitic trematode Schistosoma mansoni elicits such effects. The focus of this study was to investigate which developmental stages of schistosome infection confer suppression of allergic airway inflammation (AAI) using ovalbumin (OVA) as a model allergen. Moreover, we assessed the functional role and localization of infection-induced CD4+Foxp3+ regulatory T cells (Treg) in mediating such suppressive effects. Therefore, AAI was elicited using OVA/adjuvant sensitizations with subsequent OVA aerosolic challenge and was induced during various stages of infection, as well as after successful anti-helminthic treatment with praziquantel. The role of Treg was determined by specifically depleting Treg in a genetically modified mouse model (DEREG) during schistosome infection. Alterations in AAI were determined by cell infiltration levels into the bronchial system, OVA-specific IgE and Th2 type responses, airway hyper-sensitivity and lung pathology. Our results demonstrate that schistosome infection leads to a suppression of OVA-induced AAI when mice are challenged during the patent phase of infection: production of eggs by fecund female worms. Moreover, this ameliorating effect does not persist after anti-helminthic treatment, and depletion of Treg reverts suppression, resulting in aggravated AAI responses. This is most likely due to a delayed reconstitution of Treg in infected-depleted animals which have strong ongoing immune responses. In summary, we conclude that schistosome-mediated suppression of AAI requires the presence of viable eggs and infection-driven Treg cells. These data provide evidence that helminth derived products could be incorporated into treatment strategies that specifically target suppression of immune responses in AAI by inducing Treg cells.

Modeling Susceptibility versus Resistance in Allergic Airway Disease Reveals Regulation by Tec Kinase Itk

Murine models of allergic asthma have been used to understand the mechanisms of development and pathology in this disease. In addition, knockout mice have contributed significantly to our understanding of the roles of specific molecules and cytokines in these models. However, results can vary significantly depending on the mouse strain used in the model, and in particularly in understanding the effect of specific knockouts. For example, it can be equivocal as to whether specific gene knockouts affect the susceptibility of the mice to developing the disease, or lead to resistance. Here we used a house dust mite model of allergic airway inflammation to examine the response of two strains of mice (C57BL/6 and BALB/c) which differ in their responses in allergic airway inflammation. We demonstrate an algorithm that can facilitate the understanding of the behavior of these models with regards to susceptibility (to allergic airway inflammation) (Saai) or resistance (Raai) in this model. We verify that both C57BL/6 and BALB/c develop disease, but BALB/c mice have higher Saai for development. We then use this approach to show that the absence of the Tec family kinase Itk, which regulates the production of Th2 cytokines, leads to Raai in the C57BL/6 background, but decreases Saai on the BALB/c background. We suggest that the use of such approaches could clarify the behavior of various knockout mice in modeling allergic asthma.

Hepatocyte Growth Factor Significantly Suppresses Collagen-Induced Arthritis in Mice

Hepatocyte growth factor (HGF) plays an important role in angiogenesis, cell proliferation, antifibrosis, and antiapoptosis. Moreover, recent studies have highlighted the immunosuppressive effect of HGF in animal models of allogenic heart transplantation and autoimmune myocarditis and in studies in vitro as well. We also reported that HGF significantly suppresses dendritic cell function, thus down-regulating Ag-induced Th1-type and Th2-type immune responses in allergic airway inflammation. However, the immunosuppressive effect of HGF in many other situations has not been fully clarified. In the present study, using a mouse model of collagen-induced arthritis (CIA) and experiments in vitro, we examined the effect of HGF on autoimmune arthritis and then elucidated the mechanisms of action of HGF. To achieve sufficient delivery of HGF, we used biodegradable gelatin hydrogels as a carrier. HGF suppressed Ag-induced T cell priming by regulating the functions of dendritic cells in the Ag-sensitization phase with down-regulation of IL-10. In contrast, under continuous Ag stimulation HGF induced IL-10-producing immunocytes both in vivo and in vitro. Moreover, HGF potently inhibited the development of CIA with enhancing the Th2-type immune response. We also confirmed that HGF significantly suppressed the production of IL-17 by immunocytes. These results indicate that HGF suppresses the development of CIA through different ways at different phases. They also suggest that HGF could be an attractive tool for treating patients with rheumatoid arthritis.