TREM‐1 regulates neutrophil chemotaxis by promoting NOX‐dependent superoxide production

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

article

Sankar Baruah¹  Shubha Murthy¹  Kathy Keck¹  Isabel Galvan¹  Allan Prichard²  LeeAnn H. Allen¹  Mary Farrelly¹  Julia KlesneyTait¹ 

[1] Department of Internal Medicine University of Iowa Carver College of Medicine Iowa City Iowa USA;Department of Microbiology and Immunology University of Iowa Carver College of Medicine Iowa City Iowa USA;Inflammation Program University of Iowa Carver College of Medicine Iowa City Iowa USA;Iowa City VA Healthcare System Iowa City Iowa USA

关键词: neutrophils;    granulocytes;    NADPH oxidative;    signaling cascade;    cell adhesion/recruitment/emigration;    immune response;    inflammation;    innate cell mediated immunity;    manipulation of immune response;   

DOI  :  10.1002/JLB.3VMA0918-375R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

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.

【 授权许可】

CC BY