Lee's "The Tangled Webs That Neutrophils Weave" (2004)

From Biol557

• Neutrophils are the first line of defense against bacterial infection.
• Patients with too few neutrophils (neutropenia) suffer from increased infections and sometimes death.
• Neutrophils generally phagocytize their target and then fuse the phagosome with a lysosome filled with lytic, degradative agents like oxygen radicals, cationic proteins, and lytic enzymes.
• Neutrophils can also kill bacteria before engulfing them by secreting similar degradative agents.
• Though the extracellular method of killing is faster, it can also damage local, healthy, autogeneic tissue.
• Several scientists have shown a novel method used by neutrophils to kill bacteria extracellularly without damaging local, healthy, autogeneic tissue.
• Brinkmann et al show that cytokines and bacteria-released endotoxins stimulate neutrophils to present a NET (neutrophil extracellular traps) made of DNA, histones, and granule proteins.
  • These NETs bind gram+ and gram- bacterial and show bactericidal activity.
  • The elastase part of the NETs (a granule protein) degrades bacterial virulence factors.
  • They also show that putting DNase out with NETs removes the NETs' ability to kill bacteria.
• It is postulated that NETs are used to quickly arrest and digest bacterial invaders.
• The obvious question is how neutrophils go about giving up their DNA to build these NETs (though they are fully differentiated cells that do not divide).
• The authors suggest that the neutrophils undergo an active expulsion of their DNA because the authors found no evidence of factors that would identify necrosis or apoptosis.
  • This is pretty bold, so it must be validated by direct observation.
• We know that elastase, cathepsin G, and other proteases are secreted by neutrophils to kill microbes and probably play a role in tissue remodeling and cell migration, too.
• We know there are also inhibitors of these factors that keep them from running rampant.
• However, NETs may serve to localize these degredative factors and may even serve to sequester cytokines to keep neutrophils from being overly stimulated and thus cause inflammation.
• Cystic fibrosis patients have increased sputum generation in their lungs. This sputum includes a DNA-elastase mixture that is reminiscent of NETs.
• For cystic fibrosis, inhalations of DNase is often administered because it increases pulmonary function. This seems contrary to these findings, however, because DNase arrests the antimicrobial activity of NETs and we would think that antimicrobial function would be important since patients with CF incur increased pulmonary infections.
• Perhaps, however, DNase is good because the body is actually generating too many NETs and therefore the breakdown induced by DNase allows increased pulmonary function.
  • This is plausible if we imagine that the NETs interfere with the ciliary action necessary for proper pulmonary function--the cilia being entangled in the NETs.
• There are more questions to be answered, too:
  • Do all neutrophils generate NETs?
    • If so, don't they stop the recruitment of other neutrophils and don't they make it harder for neutrophils to migrate to the site of injury?
  • How are NETs degraded upon recovery?
  • Are these NETs produced post mortem by neutrophils or while they are still living?
• We need to find out more about this amazing phenomenon.