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- Title
TREM‐1 regulates neutrophil chemotaxis by promoting NOX‐dependent superoxide production.
- Authors
Baruah, Sankar; Murthy, Shubha; Keck, Kathy; Galvan, Isabel; Farrelly, Mary; Klesney‐Tait, Julia; Allen, Lee‐Ann H.; Prichard, Allan
- Abstract
Neutrophil migration across tissue barriers to the site of injury involves integration of complex danger signals and is critical for host survival. Numerous studies demonstrate that these environmental signals fundamentally alter the responses of extravasated or "primed" neutrophils. Triggering receptor expressed on myeloid cells 1 (TREM‐1) plays a central role in modulating inflammatory signaling and neutrophil migration into the alveolar airspace. Using a genetic approach, we examined the role of TREM‐1 in extravasated neutrophil function. Neutrophil migration in response to chemoattractants is dependent upon multiple factors, including reactive oxygen species (ROS) generated either extracellularly by epithelial cells or intracellularly by NADPH oxidase (NOX). We, therefore, questioned whether ROS were responsible for TREM‐1‐mediated regulation of migration. Thioglycollate‐elicited peritoneal neutrophils isolated from wild‐type (WT) and TREM‐1‐deficient mice were stimulated with soluble and particulate agonists. Using electron paramagnetic resonance spectroscopy, we demonstrated that NOX2‐dependent superoxide production is impaired in TREM‐1‐deficient neutrophils. Consistent with these findings, we confirmed with Clark electrode that TREM‐1‐deficient neutrophils consume less oxygen. Next, we demonstrated that TREM‐1 deficient neutrophils have impaired directional migration to fMLP and zymosan‐activated serum as compared to WT neutrophils and that deletion or inhibition of NOX2 in WT but not TREM‐1‐deficient neutrophils significantly impaired direction sensing. Finally, TREM‐1 deficiency resulted in decreased protein kinase B (AKT) activation. Thus, TREM‐1 regulates neutrophil migratory properties, in part, by promoting AKT activation and NOX2‐dependent superoxide production. These findings provide the first mechanistic evidence as to how TREM‐1 regulates neutrophil migration.
- Subjects
SUPEROXIDES; NEUTROPHIL immunology; ELECTRON paramagnetic resonance spectroscopy; PROTEIN kinase B; NADPH oxidase; CHEMOTAXIS; EPITHELIAL cells
- Publication
Journal of Leukocyte Biology, 2019, Vol 105, Issue 6, p1195
- ISSN
0741-5400
- Publication type
Article
- DOI
10.1002/JLB.3VMA0918-375R