Neutrophils, the most abundant circulating white blood cells in the human body, patrol the capillary networks of the lung monitoring the airspace. Here they provide the first line of defense against invading pathogens and toxin exposures. While neutrophil migration is essential for pathogen elimination in the lung, inadvertent targeting of these cells to the airspace can result in life threatening lung damage. The long term goal of this research is to identify the molecular pathways utilized during TREM-1 (triggering receptor expressed on myeloid cells-1) dependent neutrophil migration into the airspace and leverage this information to develop therapeutic tools to prevent neutrophil-driven lung injury. TREM-1, initially discovered on human neutrophils and monocytes, serves as a critical amplifier of immune signaling. We recently discovered that neutrophil TREM-1 is required for transepithelial migration into the lung following gram negative infection. In addition to its established role in te amplification of inflammatory signaling, these findings identified a novel role for TREM-1 in neutrophil migration. During our characterization of human neutrophil migration, we identified a novel TREM-1 splice variant (TREM-1sv) protein stored in primary and secondary granules. This splice isoform is released during transepithelial migration. We also found in pilot studies that inhibition of extracellular ROS attenuates neutrophil transepithelial migration, and TREM-1 deficient neutrophils have reduced mitochondrial ROS production. In addition to a membrane isoform of TREM-1, a soluble form of the receptor has been described in human disease. However, the origin and function of this soluble molecule remain poorly understood. We hypothesize that neutrophil mitochondrial ROS and TREM-1sv modulate TREM-1 dependent transepithelial migration in the lung and that mitochondrial ROS is required for TREM-1 mediated migration. To test our hypothesis, we propose the following specific aims. 1. Determine if mitochondrial ROS is required for TREM-1 mediated neutrophil transepithelial migration. The goal of these studies is to investigate if pharmacologic and genetic modulation of mitochondrial ROS alters transepithelial migration. 2. Determine if TREM-1sv regulates ROS-driven neutrophil transepithelial migration. The goal of these studies is to determine if exogenous TREM-1 modulates the ability of neutrophils to cross the epithelial barrier either by altering neutrophil epithelial interactions or by abrogating mitochondrial ROS production. 3. Test the efficacy of TREM-1sv as a therapy to decrease neutrophil transepithelial migration in vivo. The goal of these studies is to determine if exogenous TREM-1sv can inhibit neutrophil migration into the airspace and decrease local inflammation.

Public Health Relevance

Effective neutrophil migration into the intrapulmonary airspace is essential for pathogen elimination in the lung. In this study, we will identify the mechanism by which the inflammatory system amplifier TREM-1 mediates migration of neutrophils across the epithelium in response to lung injury. Characterization of these pathways may stimulate novel therapeutics targeted at neutrophil migration to treat pneumonia and other respiratory diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL121105-02
Application #
9084608
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Harabin, Andrea L
Project Start
2015-07-01
Project End
2020-03-31
Budget Start
2016-04-01
Budget End
2017-03-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Iowa
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52246
Swatek, Anthony M; Lynch, Thomas J; Crooke, Adrianne K et al. (2018) Depletion of Airway Submucosal Glands and TP63+KRT5+ Basal Cells in Obliterative Bronchiolitis. Am J Respir Crit Care Med 197:1045-1057
Thiel, William H; Esposito, Carla L; Dickey, David D et al. (2016) Smooth Muscle Cell-targeted RNA Aptamer Inhibits Neointimal Formation. Mol Ther 24:779-787
Baruah, Sankar; Keck, Kathy; Vrenios, Michelle et al. (2015) Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules. J Immunol 195:5725-31
Xie, Qing; Klesney-Tait, Julia; Keck, Kathy et al. (2015) Characterization of a novel mouse model with genetic deletion of CD177. Protein Cell 6:117-26