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

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) andTREM-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 thatTREM-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 notTREM-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 howTREM-1 regulates neutrophil migration.

Association of TREM-1, IL-1β, IL-33/ST2, and TLR Expressions With the Pathogenesis of Ocular Toxoplasmosis in Mouse Models on Different Genetic Backgrounds

“…In this study, neutrophil infiltration and the expression levels of TREM-1, IL-33, and ST2 increased in the eyes of both B6 and BALB/c mice, and the IL-1β level was increased in B6 mice after ocular T. gondii infection, TREM-1 plays a role in regulating neutrophil chemotaxis in acute infectious diseases and is a potential biomarker for the diagnosis of infectious diseases (Cao et al, 2017). TREM-1 alters neutrophil infiltration by stimulating AKT activation and NADPH oxidase-2-dependent superoxide release (Baruah et al, 2019). Blockage of TREM-1 expressed on neutrophils and monocytes/macrophages decreases the activation of neutrophils and monocytes/macrophages and mRNA expressions of inflammation-associated genes in alcoholic liver disease of mouse model (Tornai et al, 2019).…”

Defect of Interferon γ Leads to Impaired Wound Healing through Prolonged Neutrophilic Inflammatory Response and Enhanced MMP-2 Activation

“…Thioglycolate-elicited peritoneal neutrophils were obtained from WT mice by a previously described method [39]. WT mice were intraperitoneally injected with 1.5 mL of sterile 4% thioglycolate; 12–15 h later, peritoneal lavages were performed with 10 mL PBS in each mouse.…”

Hv1/VSOP regulates neutrophil directional migration and ERK activity by tuning ROS production

“…For example, neutrophil migration toward E. coli bacteria is initiated by the binding of N‐formyl‐Met‐Leu‐Phe (fMLF; also called fMLP) to formyl‐peptide receptor (FPR) 11,12 . The resultant receptor activation induces increases in intracellular cAMP and Ca 2+ ion 13 as well as activation of protein kinase B (PKB)/Akt 14 and MAPK signaling cascades 15,16 . Orchestration of those signals enables neutrophils to migrate to infection sites.…”