Neutrophil CD14: expanding the deep vein thrombosis framework

In this issue of Blood Advances, Pandey et al 1 explore the mechanisms of neutrophil activation in the different stages of deep vein thrombosis (DVT).Their findings suggest, for the first time, that CD14 plays a role in the early phase of inferior vena cava (IVC) stenosis (see figure).DVT is a major health care concern that requires enhanced prophylaxis and treatment strategies.It is recognized as an inflammatory process, in which innate immune cells, particularly neutrophils, play a decisive role in the initiation, propagation, and resolution of thrombus.Neutrophils circulate in the bloodstream, and in response to various stimuli, expel their DNA, decondensed chromatin decorated with proteases, to form neutrophil extracellular traps (NETs).Although NETs are important in defending against pathogens by trapping extracellular bacteria and exposing them to NET-associated bactericidal molecules, they also play a key role in inducing aberrant coagulation and thrombosis. 2,3Although the relationship between neutrophils and DVT has been extensively studied, the complex interactions involved in disease pathogenesis remain poorly understood.Elevated neutrophil counts and neutrophilderived biomarkers are strongly correlated with DVT incidence and mortality in patients, thus supporting their clinical relevance. 4,5 integrating multiomics profiling, mechanistic molecular studies, and in vitro and in vivo functional approaches, the authors investigated the changes occurring to neutrophils in the early stages of flowrestricted conditions (IVC stenosis).This is the critical window during which inflammatory cues shape subsequent thrombus growth.Specifically, they detected an increase in CD14, a molecule that is largely expressed by leukocytes, which acts as a toll-like receptor 4 coreceptor for lipopolysaccharide, and can also be activated by oxidized lipids and other damage-associated molecular patterns or pathogen-associated molecular patterns. 6Importantly, Pandey et al report that granulocyte colonystimulating factor (G-CSF) levels also rose in plasma during the initial phase of IVC stenosis linking G-CSF signaling to neutrophil functional reprogramming, including an elevation in CD14 at mRNA and protein levels in neutrophils.G-CSF has been associated with thrombotic risk in clinical and experimental settings, exerting proinflammatory and prothrombotic role that influences the number and activation of circulating neutrophils under inflammatory stress.However, downstream pathways mediating these effects as well as their relationship with NET formation, are unclear. [7][8]8][9] Here, the authors showed that G-CSF induces CCAAT enhancer-binding protein alpha (C/EBP) expression and binding to the CD14 promoter in neutrophils.Thus, neutrophil recruitment was enhanced, promoting NETosis and thrombosis.C/EBP is a transcription factor that influences granulopoiesis.On the other hand, it has also been observed that C/EBP is not induced by G-CSF in hematopoietic stem cells and other precursors. 10