A Single-cell Transcriptomic Profiling Reveals the Effects of Chronic House Dust Mite Exposure on the Murine Lung Microenvironment
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE300531 | GEO | 2025/10/29
REPOSITORIES: GEO
Similar Datasets
Project description:Introduction: Asthma, a chronic airway disease, is marked by allergic inflammation, hyperresponsiveness, and tissue remodeling. Influenza infections in asthma patients can cause severe exacerbations, though the underlying mechanisms remain unclear. This study investigated how pre-existing allergic inflammation affects immune responses to influenza infection in mice exposed to house dust mite (HDM). Methods: Mice were repeatedly exposed to HDM, followed by infection with influenza A virus, and were sacrificed three days post-infection. Plasma was analyzed for HDM-specific immunoglobulins, while lung tissue was used for immune cell flow cytometry and RNA sequencing analysis. Results: HDM exposure induced allergic inflammation, evidenced by more HDM-specific IgE, IgG1, IgG2, eosinophils, neutrophils, Th1, and Th17 cells compared to controls. Upon influenza infection, the effects of HDM and influenza co-infection interacted, showing fewer Th1 cells and regulatory T cells and more Th2 cells compared to mice exposed to influenza virus alone. Interestingly, RNA-seq analysis revealed less upregulation of Th1-related genes and antiviral pathways in co-exposed mice, suggesting impaired Th1 immunity and antiviral responses. Conclusion: Pre-existing allergic inflammation significantly altered immune responses in mice coinfected with influenza, revealing underdeveloped antiviral responses as early as three days post-infection. These findings may explain the increased susceptibility of patients with asthma to severe viral diseases.
2025-04-30 | GSE293097 | GEO
Project description:The increasing prevalence of chronic allergic lung diseases demands development of new preventative strategies. We previously demonstrated that therapeutic inhalation of the synergistic agents ODN M362, a TLR9 ligand, and Pam2CSK4, a TLR2/6 ligand (collectively, “Pam2ODN”) protects mice against both infectious challenges and allergic lung disease models, including allergic inflammation caused by mouse house dust mite (HDM) extract. By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects the interactions of lung epithelial cells, dendritic cells, and T cells to prevent lung eosinophilic inflammation has not been established. In the present study, we show that a single inhaled dose of Pam2ODN prior to HDM sensitization reduces Th2 polarization of airway CD4+ T cells without affecting the immune responses of Th1 or Treg cells. Furthermore, Pam2ODN pre-treatment inhibits recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional type 2 migratory dendritic cells (DC2s) while preventing HDM-induced decrease of conventional type 1 migratory dendritic cells (DC1s). Bulk RNA-seq of whole lung homogenates reveals that Pam2ODN pretreatment restricts the expression of HDM sensitization-induced proinflammatory transcripts. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells where many proinflammatory transcripts, pathways and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced lung proallergic DC cytokines while maintaining the population of protective DC1s, which prevents lung injury and Th2 polarization. Collectively, our findings suggest that the development of Th2-induced chronic allergic lung diseases may be mitigated by lung epithelium-targeted immunomodulatory strategies.
2025-06-15 | GSE299705 | GEO
Project description:The increasing prevalence of chronic allergic lung diseases demands development of new preventative strategies. We previously demonstrated that therapeutic inhalation of the synergistic agents ODN M362, a TLR9 ligand, and Pam2CSK4, a TLR2/6 ligand (collectively, “Pam2ODN”) protects mice against both infectious challenges and allergic lung disease models, including allergic inflammation caused by mouse house dust mite (HDM) extract. By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects the interactions of lung epithelial cells, dendritic cells, and T cells to prevent lung eosinophilic inflammation has not been established. In the present study, we show that a single inhaled dose of Pam2ODN prior to HDM sensitization reduces Th2 polarization of airway CD4+ T cells without affecting the immune responses of Th1 or Treg cells. Furthermore, Pam2ODN pre-treatment inhibits recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional type 2 migratory dendritic cells (DC2s) while preventing HDM-induced decrease of conventional type 1 migratory dendritic cells (DC1s). Bulk RNA-seq of whole lung homogenates reveals that Pam2ODN pretreatment restricts the expression of HDM sensitization-induced proinflammatory transcripts. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells where many proinflammatory transcripts, pathways and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced lung proallergic DC cytokines while maintaining the population of protective DC1s, which prevents lung injury and Th2 polarization. Collectively, our findings suggest that the development of Th2-induced chronic allergic lung diseases may be mitigated by lung epithelium-targeted immunomodulatory strategies.
2025-06-15 | GSE299558 | GEO
Project description:The increasing prevalence of chronic allergic lung diseases demands development of new preventative strategies. We previously demonstrated that therapeutic inhalation of the synergistic agents ODN M362, a TLR9 ligand, and Pam2CSK4, a TLR2/6 ligand (collectively, “Pam2ODN”) protects mice against both infectious challenges and allergic lung disease models, including allergic inflammation caused by mouse house dust mite (HDM) extract. By preventing sensitization, Pam2ODN reduces HDM-induced eosinophilic and lymphocytic inflammation. How Pam2ODN affects the interactions of lung epithelial cells, dendritic cells, and T cells to prevent lung eosinophilic inflammation has not been established. In the present study, we show that a single inhaled dose of Pam2ODN prior to HDM sensitization reduces Th2 polarization of airway CD4+ T cells without affecting the immune responses of Th1 or Treg cells. Furthermore, Pam2ODN pre-treatment inhibits recruitment of lung monocyte-derived dendritic cells (moDCs) and conventional type 2 migratory dendritic cells (DC2s) while preventing HDM-induced decrease of conventional type 1 migratory dendritic cells (DC1s). Bulk RNA-seq of whole lung homogenates reveals that Pam2ODN pretreatment restricts the expression of HDM sensitization-induced proinflammatory transcripts. This tolerogenic effect is also reflected at the single-cell level in lung epithelial cells where many proinflammatory transcripts, pathways and chromatin accessibility are inhibited. These results indicate that Pam2ODN reprograms lung epithelial cells to attenuate allergen-induced lung proallergic DC cytokines while maintaining the population of protective cDC1s, which prevents lung injury and Th2 polarization. Collectively, our findings suggest that the development of Th2-induced chronic allergic lung diseases may be mitigated by lung epithelium-targeted immunomodulatory strategies.
2025-06-15 | GSE299556 | GEO
Project description:Levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in mouse models of asthma. Wild type and DDAH1-transgenic mice were challenged with PBS or house dust mite (HDM). Airway inflammation was assessed by bronchoalveolar lavage (BAL) total and differential cell counts. Gene expression in lungs was determined by RNA-Seq and RT-quantitative PCR (qPCR). The expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in serum and BAL fluid were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in inducible nitric oxide synthase (iNOS) signaling pathway in PBS-treated DDAH1 transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1 transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 in airway epithelial cells may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses. mRNA profiles of WT and DDAH1-transgenic mice treated with PBS or house dust mite (HDM).
2013-12-03 | E-GEOD-49047 | biostudies-arrayexpress
Project description:Unraveling the diversity of Th2 effector cells subsets may help us to understand their pathogenic role in Type-2 associated inflammatory disorders, including allergic diseases and helminth infections. To characterize the heterogeneity and function of these effector Th2 cells, we analyzed 47 subjects’ PBMCs [23 filarial-infected (Fil+) with or without coincident HDM sensitization (Fil+HDM+ n=12; Fil+HDM-, n=11) and 24 subjects without filarial infection (Fil-) (Fil-HDM+ n=12; and Fil-HDM-, n=12) using multiparameter flow cytometry and two-level FlowSOM analysis. The frequency of 3 memory CD4+ T cell clusters, including CCR4+CCR6+CRTH2- (subset 1), CCR4+CCR6-CRTH2+ (subset 2), and CCR6+CCR4+CRTH2+ (subset 3) were markedly enriched among Fil+ subjects. The functional characterization indicated subset 2 and 3 as distinct Th2 cytokine producers, which together were responsible for the majority of IL-4, IL-5, or IL-13 produced among the Fil+ subjects. These subsets were sorted and analyzed by multiomic single cell RNA profiling. Indeed, both subset 2 and subset 3 presented features of pathogenic Th2 effector cells based on their single cell molecular signature, including downregulation of cd27 and high expression levels of itga4, il-17rb, hpgds, klrb1, ptgdr2, il-9r, il-4, il5 and il-13 genes when compared with conventional Th2 cells from healthy controls. When the Fil+ subjects were divided based on allergic status, the Fil+HDM+ subjects had an expansion of both subset 2 (3.19% vs 1.28%, p=0.001) and subset 3 (0.39% vs 0.15%, p=0.002) Th2 cells when compared with Fil+HDM-. Gene expression analysis further demonstrated that concomitant HDM sensitization in the presence of filarial infection reshaped the molecular program of these pathogenic effector Th2 subsets by even further upregulating the expression of gata3, il17rb, clrf2, and klrb1. Notably, Fil+HDM+ patients’ cells showed higher responsiveness to filarial or HDM antigenic stimulation, producing even higher levels of IL-4, IL-5 and IL-13 when compared with Fil+HDM- patients. This distinct molecular and functional program of Th2 effector cells subsets sheds new light on the Th2 cell plasticity and their contribution to immune regulation in helminth infection and allergic diseases.
2024-05-29 | GSE240865 | GEO
Project description:Background: A specific subset of regulatory IL-10 producing B cells has been extensively studied in autoimmune and inflammatory pathologies. These cells are able to constrain exacerbated inflammation by inhibiting T cell mediated responses and maturation of antigen presenting cells. In allergic diseases, observations that increase of regulatory B cells is necessary for allergen tolerance suggest that development of allergic asthma would be associated with a defect in the regulatory B cells compartment. Objective: We sought to (i) characterize regulatory IL-10+ regulatory B cell subset in Balb/c mice by microarray and flow cytometry and (ii) investigate their regulatory capacity in vivo in a house dust mite model of allergic asthma. Results: We identified an IL-10 producing B cells subset able to control T cell proliferation in vitro in both control and asthmatic mice. This subset is decreased in allergic mice. IL-10+ Breg cells express high levels of CD9 and upregulate CD70 and CD73 after activation. Expression of CD9 allows identifying more than 50% of Bregs. Interestingly CD9+ B cells inhibit TH2-TH17 allergic airway inflammation in vivo after adoptive transfer in an IL-10 dependent manner. Conclusions: Herein, we demonstrate that induction of allergic asthma dampens the generation of Bregs contributing to exacerbated airway inflammation. We identified a distinct CD9+ Breg-cell population decreased in lung of HDM mice and able to control asthma and allergic airway inflammation by producing IL-10 after adoptive transfer. This study points B cells as an interesting therapeutic target in allergic asthma. IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) in control mice + IL-10+ B cells (n=3) and 3 IL-10- B cells (n=3) from asthmatic allergic (HDM) mice
2015-03-01 | E-GEOD-57772 | biostudies-arrayexpress
Project description:Memory helper T cells provide long-lasting host defeMemory helper T cells provide long-lasting host defense against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders. against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2 hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.
2018-08-21 | GSE114921 | GEO
Project description:While the pathogenesis of asthma is mainly orchestrated by antigen-specific Th2 cells and their cytokines, recent findings indicate the involvement of other subsets of helper T cells including Th17 cells. Previous studies have shown that IL-22, one of Th17 cell-related cytokines, plays multiple roles in regulating allergic airway inflammation; however, the mechanism underlying the Il-22-mediated regulation remains unclear. Here, we show that allergic airway inflammation upon intratracheal administration of house dust mite extract (HDM), a representative allergen, were exacerbated in IL-22-deficient mice. To address the molecular mechanisms by which IL-22 inhibits the development of HDM-induced allergic airway inflammation, we next performed an unbiased comprehensive screening of genes induced by IL-22 administration in the lung by RNA-seq analysis.
2017-08-10 | GSE100858 | GEO
Project description:Defective interleukin-6 (IL-6) signaling has been associated with Th2 bias and elevated IgE. However, the underlying mechanism by which IL-6 may prevent the development of Th2-driven diseases remains unknown. Using a model of house-dust-mite (HDM)-induced Th2 differentiation and allergic airway inflammation, we show here that IL-6 signaling in allergen-specific T cells was required to prevent Th2 development and subsequent IgE response and allergic inflammation. Th2 cell lineage commitment required strong sustained IL-2 signaling. Importantly, we found that IL-6 turned off IL-2 signaling during early T cell activation and thus inhibited Th2 cell priming. Mechanistically, we found that IL-6-driven inhibition of IL-2 signaling in responding T cells was mediated by upregulation of suppressor of cytokine signaling 3 (SOCS3). Therapeutically, this mechanism can be mimicked by JAK1 inhibition. Collectively, our results identify an unrecognized mechanism that prevents the development of unwanted Th2 cell responses and associated diseases and outline potential preventive interventions.
2023-04-07 | GSE212158 | GEO