A NET Outcome

Abstract

Neutrophils constitute a critical part of innate immunity and are well known for their ability to phagocytose and kill invading microorganisms. The microbicidal processes employed by neutrophils are highly effective at killing most ingested bacteria and fungi. However, an alternative non-phagocytic antimicrobial mechanism of neutrophils has been proposed whereby microorganisms are eliminated by neutrophil extracellular traps (NETs). NETs are comprised of DNA, histones, and antimicrobial proteins extruded by neutrophils during NETosis, a cell death pathway reported to be distinct from apoptosis, phagocytosis-induced cell death, and necrosis. Although multiple laboratories have reported NETs using various stimuli in vitro, the molecular mechanisms involved in this process have yet to be definitively elucidated, and many questions regarding the formation and putative role or function of NETs in innate host defense remain unanswered. It is with these questions in mind that we provide some reflection and perspective on NETs and NETosis.

Keywords: apoptosis; inflammation; necrosis; neutrophil; phagocytosis.

Figure 1

Possible outcomes of the interaction of microbes with neutrophils. Phagocytosis and killing of microorganisms by neutrophils (polymorphonuclear leukocyte, PMN) triggers host cell apoptosis and ultimate removal by macrophages (MΦ) or dendritic cells. This process promotes resolution of the inflammatory response (A). Pathogenic microbes such as Staphylococcus aureus can cause lysis of PMN after phagocytosis, thereby facilitating escape/dissemination of the invading pathogen and release of cytotoxic molecules that cause host tissue damage and disease (B). NETs ensnare and may kill microbes, but there is accompanying lysis of neutrophils and release of cytotoxic molecules that are known to cause host tissue damage and promote inflammatory disease. In this regard, the outcome of NETosis and the formation of NETs should be similar to that in (B; i.e., disease; C).