RTG 2408 - Maladaptive processes across physiological barriers in chronic diseases

Jun.-Prof. Dr. Sascha Kahlfuß

Jun.-Prof. Dr. Sascha Kahlfuß

Institute of Molecular and Clinical Immunology
Project Leader
Project 12
Project 12

P12: Th2 cell-dependent effects on the airway epithelial barrier during chronic asthma

AK

Anna Krone

PhD Student

                                

SK

Sascha Kahlfuß

Project Leader

 

Allergic asthma is characterized by chronic inflammation and airway remodeling, which involves epithelial barrier dysfunction, fibrosis, goblet cell hyperplasia/metaplasia, smooth muscle thickening and increased endothelial permeability. Repetitive chronic exposure to allergens such as from house dust mites (HDM) mediates a dysregulation of the airway epithelia including alveolar type II cells (AECsII). This cumulates in Th2 cell activation and the amplification of asthmatic airway inflammation. However, how the intercellular communication between alveolar epithelial cells and Th2 cells contributes to the fixation of especially chronic asthmatic airway inflammation is not fully understood yet. We hypothesize that in chronic asthma, metabolites provide a specific metabolic environment within the lung, which favors chronic inflammation and fixation of the disease by changing the epithelial barrier. To address this question project 12 will use mice with a conditional deletion of a subclass of lipid receptors in T cells and analyze their potential to develop asthmatic airway inflammation using an acute and a subacute (chronic) HDM lung inflammation model. From these mice, we will isolate T cells and AECsII (cooperation with project 2), analyze their transcriptome by bulk and single cell RNA sequencing (scRNAseq) and study gene regulation by single cell Assay for Transposase-Accessible Chromatin with high-throughput sequencing (scATACseq). Further, we will investigate whether the T cell-specific deletion of certain lipid receptors alters the epithelial barrier integrity during chronic asthmatic airway inflammation (cooperation with Project 4 and Project 8). The ultimate goal of project 12 will be to understand the detailed molecular mechanisms, epigenetic regulation and signaling networks in AECsII (in cooperation with Projekt 1) that are affected by lipid signaling in T cells during the fixation of chronic asthma.  

 TP12Th2 cell-dependent effects on the airway epithelial barrier during chronic asthma. 1) Components of HDM (Derp1, Derp2, LPS, ß-glucan) acutely activate receptors (Dectin-1, TLR2, TLR4, PAR2) on AECsII. Proteases of HDM destroy gap junctions and antigenic HDM determinants are phagocytosed by DCs and presented in mediastinal lymph nodes to naïve T cells.  HDM-primed T cells differentiate into Th2 cells and migrate to the lung. 2) Here, Th2 cells secrete IL-4, IL-5, and IL-13, which mobilize eosinophils to the airways and mediate the production of HDM-specific IgE. 3) Chronic asthmatic airway inflammation through repetitive stimulation with HDM extract. 4) Metabolites such as lipids activate lipid receptors on lung Th2 cells. 5) Lipid receptors on Th2 cells are important for their pathogenic potential in mediating asthma and for the interaction between Th2 cells and the alveolar epithelia during the establishment of chronic inflammation (hypothesis). Abbreviations: HDM, house dust mites; DC, Dendritic cell; Th2 cell, T helper 2 cell; AECII, Alveolar type II cell.  

Photos: M. Schubert/University Hospital Magdeburg

Medical Doctor Project 6

MD6: Molecular interplay of Th2 cells and the airway epithelium on the transcriptome of alveolar type II cells during asthma 

TF

Tobias Franz

MD Student

                                

SK

Sascha Kahlfuß

Project Leader

 

 

Allergic asthma is an inflammatory respiratory disease and one of the most common chronic disorders causing alterations of the airway barrier integrity. During the disease pathogenesis, allergens, e.g. from house dust mites (HDMs), evoke a maladaptation of the airway epithelia as HDM components activate receptors on airway epithelial cells (e. g. Dectin-1, TLR2, TLR4, PAR2) and destroy gap junctions between them. Consequently, airway epithelial cells produce specific cytokines including IL-25, IL-33 and thymic stromal lymphopoietin (TSLP). The latter induce an immune response that involves innate but also adaptive immune cells such as T helper (Th)2 cells. We hypothesize that Th2 cells, their metabolic fitness, and their ability to communicate with other immune cells and local structural cells in the lung may play a central role in maladaptive processes of the airway epithelia during chronic asthmatic airway inflammation. Therefore, we here will elucidate the intercellular communication of alveolar epithelial cells and Th2 cells during asthmatic airway inflammation with a special focus on analyzing the transcriptional profile of airway epithelial type II cells (AECsII) during acute and chronic asthmatic airway inflammation.

MD06

Intercellular communication between Th2 cells and airway epithelial type II cells during acute and chronic asthmatic airway inflammation. HDM proteases disrupt the airway epithelial barrier. Thereafter, HDM antigens are phagocytosed by dendritic cells (DCs) and subsequently presented in mediastinal lymph nodes to naïve T cells. HDM-primed T cells differentiate into Th2 cells, produce Th2 cytokines (IL-4, IL-5, IL-13) and migrate to the lung, where they promote a disease-amplifying micromilieu. Th2 cell cytokines mediate eosinophil recruitment, airway hyperresponsiveness, and mucus production. During the pathogenesis of allergic asthma, Th2 cells interact with airway epithelial type II cells (AECsII). How this communication affects the transcriptional fixation and maladaptation of AECsII during chronic asthma will be addressed in this project.

Photos: M. Schubert/University Hospital Magdeburg

Medical Doctor Project 7

MD7: Epigenetic perpetuation of chronic asthma in airway epithelial type II cells 

JN

Jonas Negele

MD Student

                                

SK

Sascha Kahlfuß

Project Leader

 

 

The development of allergic asthma is associated with specific genetic risk factors, smoking and obesity. Currently, allergic asthma affects approximately 300 million people worldwide, which creates a significant burden to our healthcare system. The disease pathogenesis involves the sensitization and reexposure to environmental allergens such as animal hair, pollen or components of house dust mites (HDM). During chronic asthmatic airway inflammation, the lung microenvironment, which is evoked by the cellular crosstalk of T helper (Th)2 cells and the airway epithelium including airway epithelial type II cells (AECsII), induces a barrier dysregulation, goblet cell metaplasia/hyperplasia, subepithelial fibrosis, increased endothelial permeability and smooth muscle cell thickening. In our project we hypothesize that the specific disease-promoting microenvironment during asthmatic airway inflammation alters the airway epithelial barrier and mediates the perpetuation of chronic lung inflammation by epigenetic mechanisms in AECsII. To experimentally address this question, we induce acute and chronic HDM-induced asthmatic airway inflammation in mice to ultimately study the mechanisms of chronic epigenetic fixation of the disease in AECsII by ATAC sequencing. In addition, we seek to unravel the intracellular signaling pathways in AECsII that are involved during the establishment of chronic allergic lung inflammation.
MD07

Pathogenesis of HDM-induced asthma. Protease-containing HDM sensitize the airway epithelium via TLR2, TLR4, Dectin-1 and PAR2 and cause epithelial damage. Airway epithelial cells secrete the epithelial-derived factors IL-25, IL-33 and TSLP, so-called alarmins, which initiate type 2 immunity, due to activation of APCs. Naïve T cells differentiate to Th2 cells and migrate to the subepithelial layer. By the production of type 2 cytokines (IL-4, IL-5, IL-9 and IL-13) Th2 cells recruit eosinophils and induce isotype switch and thus IgE production. The disease-promoting milieu cumulates in an epithelial barrier dysfunction and epigenetic fixation of the chronic lung disease. The latter and the intracellular signaling events in airway epithelial cells that are involved in these processes will be investigated in this project. Abbreviations: AECsII, Airway epithelial type II cells; APC, Antigen-presenting cell; HDM, House dust mites; IgE, Immunoglobulin E; IL, Interleukin; PAR, Protease-activated receptor; Th2 cell, T helper 2 cell; TLR, Toll-like receptor; Tn, naïve T cell; TSLP, Thymic stromal lymphopoietin.

Photos: M. Schubert/University Hospital Magdeburg

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