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The production of neutrophil extracellular traps (NETs) is a process that enables neutrophils to help catch and kill bacteria. However, increasing evidence suggests that this process might also occur in noninfectious, sterile inflammation. In this Review, we describe the role of NETosis in autoimmunity, coagulation, acute injuries and cancer, and discuss NETs as potential therapeutic targets. Furthermore, we consider whether extracellular DNA is always detrimental in sterile inflammation and whether the source is always NETs., Author(s): Selina K Jorch [1]; Paul Kubes (corresponding author) [1, 2] Neutrophil extracellular traps (NETs) are structures of chromatin filaments coated with histones, proteases and granular and cytosolic proteins, and [...]

Staphylococcal superantigens are pyrogenic exotoxins that cause massive T cell activation leading to toxic shock syndrome and death. Despite the strong adaptive immune response induced by these toxins, infections by superantigen-producing staphylococci are very common clinical events. We hypothesized that this may be partly a result of staphylococcal strains having developed strategies that downregulate the T cell response to these toxins. Here we show that the human interleukin-2 response to staphylococcal superantigens is inhibited by the simultaneous presence of bacteria. Such a downregulatory effect is the result of peptidoglycan-embedded molecules binding to Toll-like receptor 2 and inducing interleukin-10 production and apoptosis of antigen-presenting cells. We corroborated these findings in vivo by showing substantial prevention of mortality after simultaneous administration of staphylococcal enterotoxin B with either heat-killed staphylococci or Staphylococcus aureus peptidoglycan in mouse models of superantigen-induced toxic shock syndrome., S. aureus is a common human commensal organism, present in the upper respiratory tract of 25-50% of the population (1). It is also one of the most frequent pathogens, being [...]

It has been known for many years that neutrophils and platelets participate in the pathogenesis of severe sepsis, but the inter-relationship between these players is completely unknown. We report several cellular events that led to enhanced trapping of bacteria in blood vessels: platelet TLR4 detected TLR4 ligands in blood and induced platelet binding to adherent neutrophils. This led to robust neutrophil activation and formation of neutrophil extracellular traps (NETs). Plasma from severely septic humans also induced TLR4-dependent platelet-neutrophil interactions, leading to the production of NETs. The NETs retained their integrity under flow conditions and ensnared bacteria within the vasculature. The entire event occurred primarily in the liver sinusoids and pulmonary capillaries, where NETs have the greatest capacity for bacterial trapping. We propose that platelet TLR4 is a threshold switch for this new bacterial trapping mechanism in severe sepsis., Author(s): Stephen R Clark [1, 6]; Adrienne C Ma [1, 6]; Samantha A Tavener [1]; Braedon McDonald [1]; Zahra Goodarzi [1]; Margaret M Kelly [1, 2]; Kamala D Patel [1, [...]

As babies leave their mothers' wombs, they are colonized by commensal bacteria. A new study shows that these microbes in a newborn's gut can promote an increase in circulating neutrophils that can guard the body from infections. Altering a neonate's gut microbiota with perinatal antibiotic treatment can impair neutrophils, leaving the newborn vulnerable to attack by harmful bacteria (pages 524-530)., Globally, around 4 million newborn babies die yearly due to sepsis (1). Prolonged use of antibiotics is currently under clinical practice in the interest of preventing early-onset sepsis in newborns [...]

Using a novel flow chamber assay system and whole blood, we show that leukocytes from septic individuals have a four-fold elevation of adhesion, but not rolling, on a P-selectin/β2-integrin substrate. Most leukocytes from septic patients (but not healthy controls) that bound vascular cell adhesion molecule 1 (VCAM-1) were neutrophils. All adhesion was inhibited with an antibody specific for the VCAM-1 ligand α4-integrin. The α4-integrin was present on neutrophils from septic patients but not on neutrophils from patients with localized bacterial infections. The plasma milieu of septic patients was sufficient to induce neutrophils from healthy subjects to bind VCAM-1 under flow conditions. This is the first description of α4-integrin/VCAM-1 pathway of neutrophil recruitment in human disease. This pathway may provide a new therapeutic target to reduce inappropriate neutrophil adhesion without altering the normal yet critical β2-integrin?mediated adhesive function of neutrophils. [ABSTRACT FROM AUTHOR]