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Ly6G+Nur77+ macrophages initiate the type-2 immune response to allergens in the lung

ABSTRACT: The mechanisms of allergen sensing and type 2 immune response initiation remain unclear. Using a house dust mite (HDM)-induced allergic airway model, we demonstrated that host detection of protease activity in HDM was crucial for initiating T helper type 2 (Th2) responses. This process was driven by the major allergen Der p 1, a cysteine protease, which was sensed by protease-activated receptor 2 (PAR2) on a novel population of perivascular lung macrophages expressing Ly6G and nuclear receptor Nur77. These macrophages required PAR2 and Nur77 for activation and accumulation and regulated conventional dendritic cell (mDC) migration to draining mediastinal lymph nodes (mLN) via cysteinyl leukotriene (CysLTs) production. CysLTs enhanced CCR7-driven migration of mDCs toward its ligand, CCL21, facilitating arrival to mLNs for T cell priming and expansion. Inhibiting CysLTs biosynthesis reduced mDC migration and dampened Th2 allergic responses, highlighting new therapeutic paths and mechanisms in type 2 immunity.

ORGANISM(S): Mus musculus

PROVIDER: GSE305119 | GEO | 2025/12/10

REPOSITORIES: GEO

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			Action	DRS
		Other
	GSE305119_C57BL-6J_mouse_lung_Ly6g_macrophage_nonClassical_monocyte_integrated_seuratv5.rds	Other
	GSE305119_RAW.tar	Raw
	filelist.txt	Txt

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Similar Datasets

Ly6G+Nur77+ macrophages initiate the type-2 immune response to allergens in the lung

Project description:The mechanisms of allergen sensing and type 2 immune response initiation remain unclear. Using a house dust mite (HDM)-induced allergic airway model, we demonstrated that host detection of protease activity in HDM was crucial for initiating T helper type 2 (Th2) responses. This process was driven by the major allergen Der p 1, a cysteine protease, which was sensed by protease-activated receptor 2 (PAR2) on a novel population of perivascular lung macrophages expressing Ly6G and nuclear receptor Nur77. These macrophages required PAR2 and Nur77 for activation and accumulation and regulated conventional migratory dendritic cell (mDC) migration to draining mediastinal lymph nodes (mLN) via cysteinyl leukotriene (CysLTs) production. CysLTs enhanced CCR7-driven migration of mDCs toward its ligand, CCL21, facilitating arrival to mLNs for T cell priming and expansion. Inhibiting CysLTs biosynthesis reduced mDC migration and dampened Th2 allergic responses, highlighting new therapeutic paths and mechanisms in type 2 immunity.

2025-12-10 | GSE289548 | GEO

Ly6G+Nur77+ perivascular macrophages initiate type-2 immune responses to allergens in the lung

Project description:The mechanisms of allergen sensing and type 2 immune response initiation remain unclear. Using a house dust mite (HDM)-induced allergic airway model, we demonstrated that host detection of protease activity in HDM was crucial for initiating T helper type 2 (Th2) responses. This process was driven by the major allergen Der p 1, a cysteine protease, which was sensed by protease-activated receptor 2 (PAR2) on a novel population of perivascular lung macrophages expressing Ly6G and nuclear receptor Nur77. These macrophages required PAR2 and Nur77 for activation and accumulation and regulated conventional dendritic cell (mDC) migration to draining mediastinal lymph nodes (mLN) via cysteinyl leukotriene (CysLTs) production. CysLTs enhanced CCR7-driven migration of mDCs toward its ligand, CCL21, facilitating arrival to mLNs for T cell priming and expansion. Inhibiting CysLTs biosynthesis reduced mDC migration and dampened Th2 allergic responses, highlighting new therapeutic paths and mechanisms in type 2 immunity.

2025-12-10 | GSE291081 | GEO

Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [scRNA-Seq]

Project description:The mechanisms that guide Th2 cell differentiation in barrier tissues are unclear but important for the development of allergic asthma. Using temporal, spatial and single cell transcriptomic tracking of house dust mite (HDM) specific T cells, we describe the molecular pathways driving allergen-specific Th2 cells. Early Blimp-1 expression occurs in a subset of CD4 T cells in the lymph node prior to lung migration driven by IL-10 from allergen-specific T cells, but was not required for GATA3 upregulation. Instead, IL-2 via STAT5 was required to directly repress Bcl6 and Bach2 to support GATA3 and Blimp-1 upregulation. Loss of Blimp-1 during priming in the lymph node ablated the formation of Th2 cells that migrate to the lung, indicating early Blimp-1 promotes the population of Th2 cells with migratory capability. Spatial microniches of IL-2 in the lymph node discriminate and support these earliest Blimp-1+ migratory Th2 cells, demonstrating that lymph node localization is a primary driver of differentiation. Our findings illuminate the molecular pathways for inhaled allergens to promote Th2 cells and identify an early requirement for IL-2 mediated spatial microniches and allergen-driven IL-10 from responding T cells that drive allergic asthma.

2024-02-26 | GSE245109 | GEO

Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [Curio]

2024-02-20 | GSE245111 | GEO

Spatial microniches of IL-2 synergize with IL-10 to drive lung migratory Th2 cells in response to inhaled allergen [Spatial transcriptomics]

2024-02-20 | GSE245110 | GEO

[scRNA-seq]: Inhaled PRR Agonists Reprogram Lung Epithelial Cells to Prevent Type 2 Allergic Inflammation

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

[RNA-seq]: Inhaled PRR Agonists Reprogram Lung Epithelial Cells to Prevent Type 2 Allergic Inflammation

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

[scATAC-seq]: Inhaled PRR Agonists Reprogram Lung Epithelial Cells to Prevent Type 2 Allergic Inflammation

2025-06-15 | GSE299558 | GEO

Overexpression of Dimethylarginine Dimethylaminohydrolase 1 Attenuates Airway Inflammation in Mouse Models of Asthma

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

IL-22 inhibits allergic airway inflammation in house dust mite-induced asthma models

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

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