Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness.
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2024-01
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Abstract
Introduction
Environmental exposures and experimental manipulations can alter the ontogenetic composition of tissue-resident macrophages. However, the impact of these alterations on subsequent immune responses, particularly in allergic airway diseases, remains poorly understood. This study aims to elucidate the significance of modified macrophage ontogeny resulting from environmental exposures on allergic airway responses to house dust mite (HDM) allergen.Methods
We utilized embryonic lineage labeling to delineate the ontogenetic profile of tissue-resident macrophages at baseline and following the resolution of repeated lipopolysaccharide (LPS)-induced lung injury. We investigated differences in house dust mite (HDM)-induced allergy to assess the influence of macrophage ontogeny on allergic airway responses. Additionally, we employed single-cell RNA sequencing (scRNAseq) and immunofluorescent staining to characterize the pulmonary macrophage composition, associated pathways, and tissue localization.Results
Our findings demonstrate that the ontogeny of homeostatic alveolar and interstitial macrophages is altered after the resolution from repeated LPS-induced lung injury, leading to the replacement of embryonic-derived by bone marrow-derived macrophages. This shift in macrophage ontogeny is associated with reduced HDM-induced allergic airway responses. Through scRNAseq and immunofluorescent staining, we identified a distinct subset of resident-derived interstitial macrophages expressing genes associated with allergic airway diseases, localized adjacent to terminal bronchi, and diminished by prior LPS exposure.Discussion
These results suggest a pivotal role for pulmonary macrophage ontogeny in modulating allergic airway responses. Moreover, our findings highlight the implications of prior environmental exposures in shaping future immune responses and influencing the development of allergies. By elucidating the mechanisms underlying these phenomena, this study provides valuable insights into potential therapeutic targets for allergic airway diseases and avenues for further research into immune modulation and allergic disease prevention.Type
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Tighe, Robert M, Anastasiya Birukova, Yuryi Malakhau, Yoshihiko Kobayashi, Aaron T Vose, Vidya Chandramohan, Jaime M Cyphert-Daly, R Ian Cumming, et al. (2024). Altered ontogeny and transcriptomic signatures of tissue-resident pulmonary interstitial macrophages ameliorate allergic airway hyperresponsiveness. Frontiers in immunology, 15. p. 1371764. 10.3389/fimmu.2024.1371764 Retrieved from https://hdl.handle.net/10161/32528.
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Scholars@Duke
Robert Matthew Tighe
The research focus of the Tighe laboratory is performing pulmonary basic-translational studies to define mechanisms of susceptibility to lung injury and disease. There are three principal focus areas. These include: 1) Identifying susceptibility factors and candidate pathways relevant to host biological responses to environmental pollutants such as ozone, woodsmoke and silica, 2) Defining protective and detrimental functions of lung macrophage subsets and their cross talk with the epithelium to regulate lung injury and repair, and 3) Determining the prognostic and theragnostic efficacy of 3D lung gas exchange imaging in pulmonary fibrosis using hyperpolarized 129Xenon MRI.
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Susceptibility Factors for Environmental Lung Disease: In NIH funded studies the Tighe lab has been performing fully translational studies of lung responses to ozone. These include cell, rodent and human exposure studies to define mechanisms of susceptibility to exposure. By carefully dissecting these links, we will gain insight into how environmental pollutants acutely induce respiratory symptoms and exacerbate chronic lung diseases. This can lead to targeted therapeutics and/or identify susceptible populations. This includes exploration of genetic factors and also other metabolic and immunologic factors.
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Pulmonary Macrophage Functions and Crosstalk with Lung Epithelial Cells: The central hypothesis of this line of research is that macrophages are key regulators of the biologic responses to environmental pollutants and the development of chronic lung disease. The Tighe laboratory has pioneered the identification of novel pulmonary macrophage subsets and has defined their function in lung injury and repair. In both published work and areas of active investigation, the Tighe lab has identified macrophage subsets with unique genetic programming and function after challenges with environmental exposures such as ozone, wood smoke and silica. Since macrophages have both detrimental and protective functions, identifying these subsets offers the opportunity to understand their unique programing and function. This could allow development of targeted therapeutics that take advantage of these functions, polarize the immune responses and alleviate respiratory disease. In addition, we are focused on macrophage and epithelial crosstalk and how their combined responses regulate lung injury and repair. These studies include omics approaches with single-cell RNA sequencing, proteomics and metabolomics and lung organoids to identify unique signals between macrophages and epithelial cells.
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Using Hyperpolarized 129Xenon MRI to Define Prognosis and Therapy Responses in Pulmonary Fibrosis: In industry funded studies, the Tighe lab is focused on using a novel image modality to assess prognosis and therapeutic responses in individuals with pulmonary fibrosis. Pulmonary fibrosis is a disorder of progressive scar formation in the lung that causes increased shortness of breath and persistent coughing, frequently leading to death from respiratory failure. Presently, there are limited modalities that can assess prognosis in pulmonary fibrosis and can determine which individuals are responding to therapies. To address this, the Tighe lab, in collaboration with Dr. Bastiaan Driehuys in the Department of Radiology, is using inhaled hyperpolarized 129Xenon gas MRI to define regional differences in lung gas exchange in individuals with pulmonary fibrosis. Our preliminary data suggest that baseline characteristics of 129Xenon MRI associate with pulmonary fibrosis prognosis. In addition, we observe changes in the 129Xenon MRI metrics following initiation of pulmonary fibrosis therapies. These initial observations are being confirmed in ongoing clinical trials.
Vidyalakshmi Chandramohan
The research work in my laboratory focuses on identifying novel immunotherapeutic targets for the treatment of brain tumors, specifically glioblastoma (GBM). My previous work includes the development of the dual-specific immunotoxin (IT) D2C7-IT, which is currently in Phase I clinical trials in recurrent GBM (rGBM) patients. My current research seeks to identify novel strategies to enhance the efficacy of D2C7-IT and other GBM-targeted cytotoxic therapies. In conjunction with this, my research includes the investigation of immune-related biomarkers to predict the clinical outcome of D2C7-IT therapy in patients with GBM.
Purushothama Rao Tata
Lung regeneration
Lung stem cells
Cell plasticity
Organoid models
Lung Fibrosis
Single Cell Biology
Jennifer Leigh Ingram
Dr. Ingram's research interests focus on the study of airway remodeling in human asthma. Proliferation, migration, and invasion of airway fibroblasts are key features of airway remodeling that contribute to diminished lung function over time. Dr. Ingram uses molecular biology approaches to define the effects of interleukin-13 (IL-13), a cytokine abundantly produced in the asthmatic airway, in the human airway fibroblast. She has identified important regulatory functions of several proteins prevalent in asthma that control fibroblast growth and pro-fibrotic growth factor production in response to IL-13. By understanding these pathways and their role in human asthma and the chronic effects of airway remodeling, novel treatment strategies may be developed.
Michael Dee Gunn
Lab History
The lab started with our discovery of the lymphoid chemokines, which regulate the migration of lymphocytes and dendritic cells to and within secondary lymphoid organs. We identified the chemokine (CCL21) that mediates the entry of naïve T cells and activated dendritic cells into lymph nodes and the chemokine (CXCL13) that mediates the entry of B cells into lymphoid follicles. Our focus then shifted to understanding how specific cell types, primarily dendritic cells, and cell migration events regulate immune responses. We identified murine plasmacytoid dendritic cells; the cell type that causes pulmonary immune pathology during influenza infection; the dendritic cell type that stimulates Th1 immune responses; the cell type that induces neuronal injury in Alzheimer's disease, and the macrophage type that stimulates pulmonary hypertension. Our current work continues these basic studies while applying our findings to models of human disease.
Current Research
Development of recombinant antibodies as diagnostic reagents – Our lab has developed novel methods to generate recombinant single chain antibodies using phage display technology. We are currently using these methods to generate pathogen-specific antibodies for use in diagnostic tests for a variety of human bacterial, viral, and fungal infections. In collaboration with Duke Biomedical Engineering, we are deploying our antibodies in a novel diagnostic assay platform to develop point-of-care assays for the diagnosis of a variety of emerging pathogens. Our recently developed point-of-care assay for Ebola virus displays a sensitivity superior to PCR at a fraction of the per assay cost.
Loretta Georgina Que
My research interests focus on studying the role of nitric oxide and related enzymes in the pathogenesis of lung disease, specifically that caused by nitrosative/oxidative stress. Proposed studies are performed in cell culture and applied to animal models of disease, then examined in human disease where relevant. It is our hope that by better understanding the role of NO and reactive nitrogen species in mediating inflammation, and regulating cell signaling, that we will not only help to unravel the basic mechanisms of NO related lung disease, but also provide a rationale for targeted therapeutic use of NO.
Key words: nitrosative defense, lung injury, nitric oxide
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