Dissertation
The role of TREM-1 in allergic airway inflammation
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007843
Abstract
Asthma affects 25 million Americans, and recent advances in treatment are effective for only a portion of severe asthma patients. TREM-1, an innate receptor that canonically amplifies inflammatory signaling in neutrophils and monocytes, plays a central role in regulating lung inflammation. It is unknown how TREM-1 contributes to allergic asthma pathology. We utilized genetic mouse models and a model of allergic airway inflammation (AAI) to investigate the effects of TREM-1 ablation on AAI disease severity, type 2 immune responses, and myeloid cell function.
To determine the role of TREM-1 in AAI, WT and Trem1/3-/- mice were sensitized on days 0 and 7 by intraperitoneal injection of ovalbumin and aluminum hydroxide adjuvant. They were then exposed to nebulized ovalbumin on days 16-18. On day 19, Trem1/3-/- mice demonstrated fewer eosinophils in the airway and lung tissue, fewer TH2 cells in the airway, and lower concentrations of the type 2 cytokines IL-4 and IL-5, suggesting that TREM-1 promotes development of type 2 immune responses. Importantly, Trem1/3-/- mice were also protected from airway hyperreactivity and increased airway resistance in response to methacholine challenge. Further investigation of T cell activation following antigen sensitization revealed lower proportions of GATA3+ TH2 cells within the mediastinal lymph nodes of Trem1/3-/- mice. The rate of T cell GATA3 expression was also reduced in an in vitro coculture model of naïve CD4 T cells and CD11c+ antigen presenting cells. In contrast, T cell activation and division were not impaired in the absence of TREM-1 both in vitro and in vivo. Finally, we detected TREM-1 surface expression on lung MHCII+ CD11c+ antigen presenting cells during AAI, suggesting that these critical regulators of T cell activation and differentiation may be impacted by TREM-1 ablation.
Utilizing our AAI model, flow cytometry revealed TREM-1+ eosinophils in the lung tissue and airway during AAI. TREM-1 expression was restricted to recruited, inflammatory eosinophils identified by CD101 and CD11c expression. Expression of TREM-1 was induced on bone marrow–derived eosinophils by incubation with interleukin 33, lipopolysaccharide, or granulocyte-macrophage colony-stimulating factor. During AAI, airway TREM-1+ eosinophils were enriched for proinflammatory gene sets, including migration, respiratory burst, and cytokine production when compared to TREM-1- eosinophils. Unexpectedly, eosinophil-specific ablation of TREM-1 exacerbated airway interleukin (IL) 5 production, airway MUC5AC production, and lung tissue eosinophil accumulation. Further investigation of transcriptional data revealed apoptosis and superoxide generation–related gene sets were enriched in TREM-1+ eosinophils. Consistent with these findings, annexin V and caspase-3/7 staining demonstrated higher rates of apoptosis among TREM-1+ eosinophils compared to TREM-1− eosinophils in the AAI airway. In vitro, Trem1/3−/− bone marrow–derived eosinophils consumed less oxygen than wild-type in response to phorbol myristate acetate, suggesting that TREM-1 promotes superoxide generation in eosinophils. These data reveal protein-level expression of TREM-1 by eosinophils, define a population of TREM-1+ inflammatory eosinophils, and demonstrate that eosinophil TREM-1 restricts key features of type 2 lung inflammation.
Details
- Title: Subtitle
- The role of TREM-1 in allergic airway inflammation
- Creators
- Jayden L Bowen
- Contributors
- Julia Klesney-Tait (Advisor)Jon Houtman (Committee Member)Josalyn Cho (Committee Member)Alejandro Comellas (Committee Member)Kevin Legge (Committee Member)Mary Wilson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Immunology
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007843
- Publisher
- University of Iowa
- Number of pages
- xiv, 215 pages
- Copyright
- Copyright 2025 Jayden Bowen
- Language
- English
- Date submitted
- 04/27/2025
- Description illustrations
- illustrations, tables, graphs
- Description bibliographic
- Includes bibliographical references (pages 168-185).
- Public Abstract (ETD)
- Allergic asthma is an obstructive lung disease affecting 8% of Americans. During allergic asthma exacerbation, inflammatory responses to inhaled allergens causes swelling, mucus production, and airway constriction that impairs airflow. The inflammation in allergic asthma is characterized by “type 2” immune cells including TH2 cells that recognize allergens and eosinophils that contribute to tissue damage and repair. Recent advances targeting type 2 immunity have improved allergic asthma treatment but are not effective for all patients. Understanding allergic asthma pathology is necessary to improve outcomes for all patients. Here we describe a role for Triggering receptor expressed on myeloid cells-1 (TREM-1) in allergic asthma pathogenesis. Total-body knockout of TREM-1 protects mice from harmful type 2 airway inflammation and production of TH2 cells is decreased. Surprisingly, eosinophils express TREM-1 protein, which has not been previously described. TREM-1 expressing eosinophils are inflammatory, recruited eosinophils that differ in protein and gene expression from eosinophils that do not express TREM-1. Further, TREM-1 is only expressed by eosinophils during inflammation and after leaving the blood stream to enter the lung. When TREM-1 is removed specifically from eosinophils, type 2 inflammation in the lung is paradoxically worsened. This suggests that the role of TREM-1 in allergic asthma may vary depending on which cell it is expressed on. Further study is warranted to understand this key inflammatory protein in asthma.
- Academic Unit
- Immunology Graduate Program
- Record Identifier
- 9984831230402771
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