Neutrophils as effectors of vascular inflammation.

Vascular inflammation underlies most forms of cardiovascular disease, which remains a prevalent cause of death among the global population. Advances in the biology of neutrophils, as well as insights into their dynamics in tissues, have revealed that these cells are prominent drivers of vascular inflammation though derailed activation within blood vessels. The development of powerful imaging techniques, as well as identification of cells and molecules that regulate their activation within vessels, including platelets and catecholamines, has been instrumental to better understand the mechanisms through which neutrophils protect or damage the organism. Other advances in our understanding of how these leucocytes exert detrimental functions on neighbouring cells, including the formation of DNA-based extracellular traps, constitute milestones in defining neutrophil-driven inflammation. Here, we review emerging mechanisms that regulate intravascular activation and effector functions of neutrophils, and discuss specific pathologies in which these processes are relevant. We argue that identification of pathways and mechanisms specifically engaged within the vasculature may provide effective therapies to treat this prevalent group of pathologies.

Developmental Analysis of Bone Marrow Neutrophils Reveals Populations Specialized in Expansion, Trafficking, and Effector Functions.

Neutrophils are specialized innate cells that require constant replenishment from proliferative bone marrow (BM) precursors as a result of their short half-life. Although it is established that neutrophils are derived from the granulocyte-macrophage progenitor (GMP), the differentiation pathways from GMP to functional mature neutrophils are poorly defined. Using mass cytometry (CyTOF) and cell-cycle-based analysis, we identified three neutrophil subsets within the BM: a committed proliferative neutrophil precursor (preNeu) which differentiates into non-proliferating immature neutrophils and mature neutrophils. Transcriptomic profiling and functional analysis revealed that preNeu require the C/EBPε transcription factor for their generation from the GMP, and their proliferative program is substituted by a gain of migratory and effector function as they mature. preNeus expand under microbial and tumoral stress, and immature neutrophils are recruited to the periphery of tumor-bearing mice. In summary, our study identifies specialized BM granulocytic populations that ensure supply under homeostasis and stress responses.